Addiction Medicine

The Biden administration has halted a Trump administration initiative that would have allowed more physicians to prescribe buprenorphine for opioid use disorder (OUD).

Under the Trump administration’s plan, many doctors would be exempt from taking a day’s training before they could prescribe buprenorphine for OUD.

On Jan. 25, 2021, citing anonymous sources, the Washington Post reported that this action by the Biden administration was likely. At the time, there were concerns about whether the Department of Health & Human Services had the legal authority to make this policy change, the Post reported. The Substance Abuse and Mental Health Services Administration subsequently announced the derailment of the buprenorphine proposal on its website.

The plan was unveiled Jan. 14 in the final days of the Trump administration. In SAMHSA’s view, the proposal was made “prematurely.” The SAMHSA statement did not detail the reasons for abandoning the Jan. 14 proposal. It had been scheduled to take effect upon publication in the Federal Register.

Instead of finalizing it in this way, the HHS said it would work with other federal agencies to “increase access to buprenorphine, reduce overdose rates and save lives.”

The HHS decision to scupper the proposal disappointed many physician groups. In a letter dated Jan. 27, several physician groups called on the Biden administration to proceed with the Trump proposal.

Under current federal law, physicians who wish to prescribe buprenorphine outside of opioid treatment programs must take an 8-hour course and receive a waiver from the Drug Enforcement Administration, the letter noted. It was signed by the American College of Emergency Physicians, the American Medical Association, and other organizations.
 

Treatment barrier

After taking the training course, it can take 60-90 days for physicians to receive the waiver. The license application can then be submitted. Physician groups argue that this so-called X-waiver requirement creates a barrier to providing medication-assisted treatment.

“Due to the stigma, some clinicians are not willing to pursue this DEA license or even engage in treatment of patients with [OUD],” the letter said.

The Trump administration’s proposal would have limited most physicians to treating no more than 30 patients with buprenorphine for OUD at any one time. This cap would not have applied to hospital-based physicians, such as those practicing emergency medicine, the HHS noted in a statement. The policy would have applied to only physicians who already have registered with the DEA.

Patrice A. Harris, MD, the immediate past president of the AMA and chair of the organization’s Opioid Task Force, was among the many physicians who supported the Trump administration proposal.

“It is estimated that more than 2 million Americans need treatment for opioid use disorder, but only a small percentage actually receive treatment,” Dr. Harris said in statement. Dr. Harris also noted that overdose deaths have reportedly accelerated during the COVID-19 pandemic.

Centers for Disease Control and Prevention data show there were more than 83,000 drug overdose deaths in the United States in the 12 months ending in June 2020. That is the highest number of overdose deaths ever recorded in a 12-month period and is an increase of more than 21%, compared with the previous year.
 

A ‘disappointment’

On Jan. 28, Dr. Harris said the decision to drop the plan was a disappointment.

“We encourage the current administration to quickly develop a path forward that removes the burdensome waiver requirement, thus allowing more physicians to prescribe this lifesaving medication,” she said in a statement sent to this news organization.

In a Jan. 26 statement, the American Society of Addiction Medicine urged Congress to eliminate the X-waiver and called for more education and training in the treatment of patients who struggle with opioids.

In the 116th session of Congress, which ended on Jan. 3, there was bipartisan support for proposed legislation to ease requirements for buprenorphine prescribing. A House bill had more than 90 Democratic and 21 Republican sponsors. A companion Senate bill had three Democratic and three Republican Sponsors, including Sen. Maggie Hassan (D-N.H.). On Jan. 25, Dr. Hassan tweeted that she would be seeking an explanation from the Biden administration if it halted the plan to ease the waiver restriction.

“Medication-assisted treatment can save lives, and the buprenorphine waiver requirement should be eliminated so that physicians can more easily prescribe it to those who need it,” she said.

Many clinicians and policy experts turned to Twitter to urge an easing of buprenorphine prescribing, using the hashtag “Xthexwaiver.”

Among them was the official who put forward the Jan. 14 proposal, Brett Giroir, MD. He served as assistant secretary for health during the Trump administration.

 

Objections

In its Jan. 25 article, the Washington Post referred to an article in Alcoholism and Drug Abuse Weekly in which a top federal official in the Trump administration objected to Dr. Giroir’s plan.

Elinore F. McCance-Katz, MD, PhD, who served as the assistant secretary of HHS for SAMHSA, had earlier proposed raising the cap for addiction experts. Alcoholism and Drug Abuse Weekly quotes Dr. McCance-Katz as saying the Trump buprenorphine proposal was “unfair to the incoming administration.”

“The Biden administration has so much work to do to get their programs and policies into place, and to do something like this at the 11th hour that could get doctors into trouble – it’s heinous,” she said in the article.

Dr. McCance-Katz had resigned before the Trump administration proposal was unveiled. On Jan. 7, she issued a public notice announcing she would resign, citing concerns about the previous day’s attack on the U.S. Capitol.

“It had been my plan to stay until the change in administration occurred, but my plans abruptly changed last evening when, on my way back from visiting an excellent residential treatment program in New York, I saw the violent takeover of the Capitol building,” she said.

On Twitter, Roland Flores, MD, an anesthesiologist and pain specialist, urged his colleagues to consider the need for more education among clinicians who treat OUD. He jousted a bit with those favoring a swift drive to “XtheXwaiver” and questioned their arguments about the burden of the current rules.

“I think ‘all this red tape’ is a little bit of an exaggeration – it’s an 8-hour online course, and an application,” Dr. Flores tweeted in one exchange. “But #XtheXwaiver is fine – it’s probably rooted in stigma. It’s unlikely to make much difference tho. The waiver wasn’t the thing keeping docs from prescribing.”

A version of this article first appeared on Medscape.com.

The Biden administration has halted a Trump administration initiative that would have allowed more physicians to prescribe buprenorphine for opioid use disorder (OUD).

Under the Trump administration’s plan, many doctors would be exempt from taking a day’s training before they could prescribe buprenorphine for OUD.

On Jan. 25, 2021, citing anonymous sources, the Washington Post reported that this action by the Biden administration was likely. At the time, there were concerns about whether the Department of Health & Human Services had the legal authority to make this policy change, the Post reported. The Substance Abuse and Mental Health Services Administration subsequently announced the derailment of the buprenorphine proposal on its website.

The plan was unveiled Jan. 14 in the final days of the Trump administration. In SAMHSA’s view, the proposal was made “prematurely.” The SAMHSA statement did not detail the reasons for abandoning the Jan. 14 proposal. It had been scheduled to take effect upon publication in the Federal Register.

Instead of finalizing it in this way, the HHS said it would work with other federal agencies to “increase access to buprenorphine, reduce overdose rates and save lives.”

The HHS decision to scupper the proposal disappointed many physician groups. In a letter dated Jan. 27, several physician groups called on the Biden administration to proceed with the Trump proposal.

Under current federal law, physicians who wish to prescribe buprenorphine outside of opioid treatment programs must take an 8-hour course and receive a waiver from the Drug Enforcement Administration, the letter noted. It was signed by the American College of Emergency Physicians, the American Medical Association, and other organizations.
 

Treatment barrier

After taking the training course, it can take 60-90 days for physicians to receive the waiver. The license application can then be submitted. Physician groups argue that this so-called X-waiver requirement creates a barrier to providing medication-assisted treatment.

“Due to the stigma, some clinicians are not willing to pursue this DEA license or even engage in treatment of patients with [OUD],” the letter said.

The Trump administration’s proposal would have limited most physicians to treating no more than 30 patients with buprenorphine for OUD at any one time. This cap would not have applied to hospital-based physicians, such as those practicing emergency medicine, the HHS noted in a statement. The policy would have applied to only physicians who already have registered with the DEA.

Patrice A. Harris, MD, the immediate past president of the AMA and chair of the organization’s Opioid Task Force, was among the many physicians who supported the Trump administration proposal.

“It is estimated that more than 2 million Americans need treatment for opioid use disorder, but only a small percentage actually receive treatment,” Dr. Harris said in statement. Dr. Harris also noted that overdose deaths have reportedly accelerated during the COVID-19 pandemic.

Centers for Disease Control and Prevention data show there were more than 83,000 drug overdose deaths in the United States in the 12 months ending in June 2020. That is the highest number of overdose deaths ever recorded in a 12-month period and is an increase of more than 21%, compared with the previous year.
 

A ‘disappointment’

On Jan. 28, Dr. Harris said the decision to drop the plan was a disappointment.

“We encourage the current administration to quickly develop a path forward that removes the burdensome waiver requirement, thus allowing more physicians to prescribe this lifesaving medication,” she said in a statement sent to this news organization.

In a Jan. 26 statement, the American Society of Addiction Medicine urged Congress to eliminate the X-waiver and called for more education and training in the treatment of patients who struggle with opioids.

In the 116th session of Congress, which ended on Jan. 3, there was bipartisan support for proposed legislation to ease requirements for buprenorphine prescribing. A House bill had more than 90 Democratic and 21 Republican sponsors. A companion Senate bill had three Democratic and three Republican Sponsors, including Sen. Maggie Hassan (D-N.H.). On Jan. 25, Dr. Hassan tweeted that she would be seeking an explanation from the Biden administration if it halted the plan to ease the waiver restriction.

“Medication-assisted treatment can save lives, and the buprenorphine waiver requirement should be eliminated so that physicians can more easily prescribe it to those who need it,” she said.

Many clinicians and policy experts turned to Twitter to urge an easing of buprenorphine prescribing, using the hashtag “Xthexwaiver.”

Among them was the official who put forward the Jan. 14 proposal, Brett Giroir, MD. He served as assistant secretary for health during the Trump administration.

 

Objections

In its Jan. 25 article, the Washington Post referred to an article in Alcoholism and Drug Abuse Weekly in which a top federal official in the Trump administration objected to Dr. Giroir’s plan.

Elinore F. McCance-Katz, MD, PhD, who served as the assistant secretary of HHS for SAMHSA, had earlier proposed raising the cap for addiction experts. Alcoholism and Drug Abuse Weekly quotes Dr. McCance-Katz as saying the Trump buprenorphine proposal was “unfair to the incoming administration.”

“The Biden administration has so much work to do to get their programs and policies into place, and to do something like this at the 11th hour that could get doctors into trouble – it’s heinous,” she said in the article.

Dr. McCance-Katz had resigned before the Trump administration proposal was unveiled. On Jan. 7, she issued a public notice announcing she would resign, citing concerns about the previous day’s attack on the U.S. Capitol.

“It had been my plan to stay until the change in administration occurred, but my plans abruptly changed last evening when, on my way back from visiting an excellent residential treatment program in New York, I saw the violent takeover of the Capitol building,” she said.

On Twitter, Roland Flores, MD, an anesthesiologist and pain specialist, urged his colleagues to consider the need for more education among clinicians who treat OUD. He jousted a bit with those favoring a swift drive to “XtheXwaiver” and questioned their arguments about the burden of the current rules.

“I think ‘all this red tape’ is a little bit of an exaggeration – it’s an 8-hour online course, and an application,” Dr. Flores tweeted in one exchange. “But #XtheXwaiver is fine – it’s probably rooted in stigma. It’s unlikely to make much difference tho. The waiver wasn’t the thing keeping docs from prescribing.”

A version of this article first appeared on Medscape.com.

The Biden administration has halted a Trump administration initiative that would have allowed more physicians to prescribe buprenorphine for opioid use disorder (OUD).

Under the Trump administration’s plan, many doctors would be exempt from taking a day’s training before they could prescribe buprenorphine for OUD.

On Jan. 25, 2021, citing anonymous sources, the Washington Post reported that this action by the Biden administration was likely. At the time, there were concerns about whether the Department of Health & Human Services had the legal authority to make this policy change, the Post reported. The Substance Abuse and Mental Health Services Administration subsequently announced the derailment of the buprenorphine proposal on its website.

The plan was unveiled Jan. 14 in the final days of the Trump administration. In SAMHSA’s view, the proposal was made “prematurely.” The SAMHSA statement did not detail the reasons for abandoning the Jan. 14 proposal. It had been scheduled to take effect upon publication in the Federal Register.

Instead of finalizing it in this way, the HHS said it would work with other federal agencies to “increase access to buprenorphine, reduce overdose rates and save lives.”

The HHS decision to scupper the proposal disappointed many physician groups. In a letter dated Jan. 27, several physician groups called on the Biden administration to proceed with the Trump proposal.

Under current federal law, physicians who wish to prescribe buprenorphine outside of opioid treatment programs must take an 8-hour course and receive a waiver from the Drug Enforcement Administration, the letter noted. It was signed by the American College of Emergency Physicians, the American Medical Association, and other organizations.
 

Treatment barrier

After taking the training course, it can take 60-90 days for physicians to receive the waiver. The license application can then be submitted. Physician groups argue that this so-called X-waiver requirement creates a barrier to providing medication-assisted treatment.

“Due to the stigma, some clinicians are not willing to pursue this DEA license or even engage in treatment of patients with [OUD],” the letter said.

The Trump administration’s proposal would have limited most physicians to treating no more than 30 patients with buprenorphine for OUD at any one time. This cap would not have applied to hospital-based physicians, such as those practicing emergency medicine, the HHS noted in a statement. The policy would have applied to only physicians who already have registered with the DEA.

Patrice A. Harris, MD, the immediate past president of the AMA and chair of the organization’s Opioid Task Force, was among the many physicians who supported the Trump administration proposal.

“It is estimated that more than 2 million Americans need treatment for opioid use disorder, but only a small percentage actually receive treatment,” Dr. Harris said in statement. Dr. Harris also noted that overdose deaths have reportedly accelerated during the COVID-19 pandemic.

Centers for Disease Control and Prevention data show there were more than 83,000 drug overdose deaths in the United States in the 12 months ending in June 2020. That is the highest number of overdose deaths ever recorded in a 12-month period and is an increase of more than 21%, compared with the previous year.
 

A ‘disappointment’

On Jan. 28, Dr. Harris said the decision to drop the plan was a disappointment.

“We encourage the current administration to quickly develop a path forward that removes the burdensome waiver requirement, thus allowing more physicians to prescribe this lifesaving medication,” she said in a statement sent to this news organization.

In a Jan. 26 statement, the American Society of Addiction Medicine urged Congress to eliminate the X-waiver and called for more education and training in the treatment of patients who struggle with opioids.

In the 116th session of Congress, which ended on Jan. 3, there was bipartisan support for proposed legislation to ease requirements for buprenorphine prescribing. A House bill had more than 90 Democratic and 21 Republican sponsors. A companion Senate bill had three Democratic and three Republican Sponsors, including Sen. Maggie Hassan (D-N.H.). On Jan. 25, Dr. Hassan tweeted that she would be seeking an explanation from the Biden administration if it halted the plan to ease the waiver restriction.

“Medication-assisted treatment can save lives, and the buprenorphine waiver requirement should be eliminated so that physicians can more easily prescribe it to those who need it,” she said.

Many clinicians and policy experts turned to Twitter to urge an easing of buprenorphine prescribing, using the hashtag “Xthexwaiver.”

Among them was the official who put forward the Jan. 14 proposal, Brett Giroir, MD. He served as assistant secretary for health during the Trump administration.

 

Objections

In its Jan. 25 article, the Washington Post referred to an article in Alcoholism and Drug Abuse Weekly in which a top federal official in the Trump administration objected to Dr. Giroir’s plan.

Elinore F. McCance-Katz, MD, PhD, who served as the assistant secretary of HHS for SAMHSA, had earlier proposed raising the cap for addiction experts. Alcoholism and Drug Abuse Weekly quotes Dr. McCance-Katz as saying the Trump buprenorphine proposal was “unfair to the incoming administration.”

“The Biden administration has so much work to do to get their programs and policies into place, and to do something like this at the 11th hour that could get doctors into trouble – it’s heinous,” she said in the article.

Dr. McCance-Katz had resigned before the Trump administration proposal was unveiled. On Jan. 7, she issued a public notice announcing she would resign, citing concerns about the previous day’s attack on the U.S. Capitol.

“It had been my plan to stay until the change in administration occurred, but my plans abruptly changed last evening when, on my way back from visiting an excellent residential treatment program in New York, I saw the violent takeover of the Capitol building,” she said.

On Twitter, Roland Flores, MD, an anesthesiologist and pain specialist, urged his colleagues to consider the need for more education among clinicians who treat OUD. He jousted a bit with those favoring a swift drive to “XtheXwaiver” and questioned their arguments about the burden of the current rules.

“I think ‘all this red tape’ is a little bit of an exaggeration – it’s an 8-hour online course, and an application,” Dr. Flores tweeted in one exchange. “But #XtheXwaiver is fine – it’s probably rooted in stigma. It’s unlikely to make much difference tho. The waiver wasn’t the thing keeping docs from prescribing.”

A version of this article first appeared on Medscape.com.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

Abrupt cessation or reduction of alcohol consumption may result in alcohol withdrawal syndrome (AWS), which is a medical emergency that can lead to serious complications when unrecognized or treatment is delayed. Symptoms of AWS include tremors, anxiety attacks, cognitive impairment, hallucinations, seizures, delirium tremens (DT), and in severe, untreated cases, death.¹ Low to moderate alcohol consumption produces euphoria and excitation via activation of glutamatergic neurotransmission, while higher concentrations produce severe intoxication via GABAergic mechanisms. Acute withdrawal unmasks the hyper-excitatory state of the brain, causing anxiety, agitation, and autonomic activation characteristic of AWS, which typically begins 1 to 3 days after the last drink.² In the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the 12-month and lifetime prevalences of AWS were 13.9% and 29.1%, respectively.³ Within the general inpatient population, AWS can be present in nearly 30% of patients; if left untreated, AWS has a 15% mortality rate, although when AWS is recognized early and treated, the mortality rate falls dramatically to 2%.⁴

AWS has most commonly been treated with benzodiazepines.⁵ However, benzodiazepines have the potential for significant adverse effects when used in older adults and in individuals with complicated medical issues, such as obstructive lung disease and sleep apnea.⁶ Anticonvulsants have been increasingly used to treat alcohol withdrawal, and their use is supported by several retrospective and prospective studies. In this article, we review the data from randomized control trials (RCTs) on the use of anticonvulsants for the treatment of AWS to see if we can make any recommendations for the use of anticonvulsants for treating AWS.

Our literature search

We searched 5 databases (PubMed, Cochrane, Medline, PsycInfo, and Embase) using the following terms: “alcohol withdrawal syndrome treatment”, “anticonvulsants”, “anti-epileptic”, “gabapentin”, “carbamazepine”, “sodium valproate”, “oxcarbazepine”, “phenytoin”, “levetiracetam”, and “lamotrigine.” We included only double-blind RCTs published between January 1, 1976 and September 30, 2016 in English-language journals or that had an official English translation. There were no restrictions on patient age or location of treatment (inpatient vs outpatient). All RCTs that compared anticonvulsants or a combination of an anticonvulsant and an active pharmacotherapeutic agent with either placebo or gold standard treatment for AWS were included. Database reviews, systematic reviews, and meta-analyses were excluded.

We identified 662 articles that met these criteria. However, most were duplicates, review articles, systematic reviews, meta-analyses, case reports, or open-label or non-randomized trials. Only 16 articles met our inclusion criteria. In the following sections, we discuss these 16 studies by medication type and in chronological order.

Gabapentin

The characteristics of the gabapentin studies included in this review are summarized in Table 1.^7-13

Bonnet et al⁷ (2003) examined 61 adults who met the clinical criteria for alcohol dependence and displayed moderate or severe AWS according to their Mainz Alcohol Withdrawal Score (MAWS ≥4). They were randomized to receive placebo or gabapentin, 400 mg 4 times a day, along with clomethiazole. The attrition rate was not significantly different between the 2 groups (P = .66). The difference in the number of clomethiazole capsules taken during the first 24 hours between the groups was small and not significant (P = .96). Analysis of MAWS over time revealed no significant main effect for group (P = .26) and a significant effect for the time variable (P < .001). The interaction between group and time was not significant (P =.4). This means that there was a significant decrease in MAWS from baseline over 48 hours, and this decrease in MAWS was considered equal for both study groups. Adverse clinical events were observed in both groups, and there was no significant difference (P = .74) between the groups. Nausea and ataxia, which are specific to gabapentin, were observed more frequently in this group.

Conclusion: The authors concluded that gabapentin, 400 mg 4 times a day, is no better than placebo in reducing the amount of clomethiazole required to treat acute AWS.⁷

Continue to: Bonnet et al

Bonnet et al⁸ (2007) also conducted a study examining 59 patients with alcohol dependence who displayed moderate or severe AWS. Participants received placebo or gabapentin, 400 mg, and a rescue medication, clomethiazole, if needed. Subsequently, a capsule of study medication was administered every 6 hours for 2 days and then tapered. During the study, mood was measured by Profile of Mood States (POMS), and subjective complaints of withdrawal were measured using the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA). Of the 59 patients, only 46 were analyzed; 5 patients dropped out, and 8 patients were missing data. Compared with the placebo group, the gabapentin group displayed less dejection, fatigue, and anger, and more vigor. Analysis of variance (ANOVA) measures revealed significant overall changes over time on all 4 scales (all P < .001). A significant (F = 3.62, df 2;43, P = .035) group × time interaction resulted exclusively for vigor. Analysis was repeated using rank-transformed data, resulting in a significant (P = .046) interaction effect. The significant increase in vigor was not apparent after tapering off gabapentin, which suggests gabapentin has a reversible effect on vigor. There was a significant (P < .001) overall decline of subjective withdrawal symptoms complaints, but no group × time interaction (P = .62). Analysis of 11 patients with comorbid mild depression revealed no significant time × group interaction for dejection, fatigue, anger, or subjective withdrawal (all P > .05). However, for vigor, the group × time interaction was significant (P = .022). Throughout the treatment, vigor scores of those mild depressive patients who received gabapentin increased to a level comparable to that of patients without a mood disorder.

Conclusion: The authors authors concluded that gabapentin was markedly more efficacious in improving vigor in the small subgroup of patients with mild depression.⁸

Myrick et al⁹ (2007) evaluated the safety and tolerability of gabapentin in patients who abused alcohol, as well as the ability of gabapentin to reduce alcohol craving and consumption. This study included 35 participants randomly assigned to receive gabapentin (n = 17) or placebo (n = 18) for 7 days. All medications were administered in standard gel caps with riboflavin, 25 mg, to assess for compliance via a laboratory-based urinary fluorescence assay. Urine samples were assessed for riboflavin at baseline and Day 6, and a reading of 1,500 ng/mL of riboflavin on Day 6 was interpreted as being compliant. Participants were required to abstain completely from drinking alcohol on Day 6 and the morning of Day 7. At the first session, the following measures were completed: demographic form, alcohol and drug section of the Structured Clinical Interview (SCID), Obsessive-Compulsive Drinking Scale, Self-Administered Alcohol Screening Test (SAAST), and Alcohol Dependence Scale (ADS); there also was collection of a urine sample for detection of abused drugs and a blood sample for liver function and general health screening.

At the second session, patients completed the psychiatric sections of the SCID and the Alcohol Craving Questionnaire, and received a physical exam. To assess the negative clinical effects of gabapentin and alcohol on the CNS, the Epworth Sleepiness Scale (ESS) and POMS were administered at baseline and on Day 6. Also, several other scales were used to identify any impact of gabapentin on acute alcohol effects and craving: the Clinical Institute Withdrawal Assessment of Alcohol, Revised (CIWA-Ar), Biphasic Alcohol Effects Scale (BAES), Subjective High Assessment Scale (SHAS), and Alcohol Urge Questionnaire (AUQ).

Conclusion: Gabapentin was well tolerated, but compared with placebo, gabapentin had no effect on alcohol stimulation (P = .75) or sedation (P = .99) as measured by the BAES. The difference in SHAS scores was also not significant (P = .19). There was also no significant reduction in craving for alcohol as measured on the AUQ scale in the gabapentin group compared with the placebo group.⁹

Continue to: Malcolm et al

Malcolm et al¹⁰ conducted an outpatient treatment study. Patients were men and women age 21 to 70 years from multiple ethnic groups. They were randomized to receive gabapentin or lorazepam; 449 patients were screened and 68 completed the follow-up. Scales used included the CIWA-Ar, Beck Depression Inventory (BDI), and ESS.

Patients receiving lorazepam reported less insomnia and more sleepiness early in treatment than patients receiving gabapentin. However, upon completing treatment and discontinuing medication administration, patients previously treated with lorazepam reported increased insomnia and daytime sleepiness, while patients previously treated with gabapentin continued to report improvements in these self-reported sleep measures. The differences between lorazepam and gabapentin were further evidenced in BDI scores at Day 5, Day 7, and Day 12 in patients who had previously experienced multiple withdrawals. Gabapentin was superior to lorazepam in reducing insomnia as assessed by BDI score, an effect that was sustained throughout the post-treatment week. Participants’ ESS scores indicated less daytime sleepiness in the gabapentin group than in the lorazepam group.

Conclusion: Among patients who abused alcohol and had a history of multiple withdrawals, lorazepam is less effective than gabapentin in reducing insomnia.¹⁰ However, this study had several limitations: <25% of individuals who were initially screened were enrolled in the study, and it used subjective tests such as BDI. Objective electrophysiologic measures of sleep and daytime sleepiness would have been very helpful.

Myrick et al¹¹ (2009) also compared gabapentin and lorazepam for treating alcohol withdrawal. One hundred patients were randomized to receive 4 days of fixed-dose taper of gabapentin or lorazepam. Patients could receive 1 of 3 gabapentin dosing regimens (600 mg/d, 900 mg/d, or 1,200 mg/d) for 3 days. Participants who were randomized to receive lorazepam were given 6 mg/d for 3 days and then tapered to 4 mg/d. Also, blinded supplemental medications (rescue packs) were given to each patient on Days 1 to 4 to treat subjective feelings of alcohol withdrawal. All patients also received thiamine for 12 days. Assessment of severity of alcohol withdrawal was measured by the CIWA-Ar. To quantify the severity of alcohol dependence and alcohol use, patients were asked to complete the ADS and Time-Line Follow-Back (TLFB) scales, respectively. Other scales administered included the BDI, Zung Anxiety Scale (ZAS), ESS, and visual analogue scales that assessed craving, ability to perform work, and need for additional medication.

There was a decrease in CIWA-Ar scores over time in all groups. High-dose gabapentin was found to be statistically superior but clinically similar to lorazepam (P = .009). Researchers also found that compared with patients who were treated with lorazepam, patients who were treated with gabapentin experienced reduced craving and anxiety/depressive symptoms, and complained of less subjective discomfort. Compared to patients who were treated with gabapentin, patients who were treated with lorazepam had higher probabilities of drinking on the first day of dose decrease (Day 2) and the second day off medication (Day 6) (P = .0002). During post-treatment, patients who were treated with gabapentin had less probability of drinking during the follow-up post-treatment period (P = .2 for 900 mg/d and P = .3 for 1,200 mg/d) compared with patients who were treated with lorazepam (P = .55).

Continue to: Conclusion

Conclusion: The researchers concluded that gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal, especially at the higher target dose (1,200 mg/d), and that compared with lorazepam, gabapentin decreased the probability of drinking during alcohol withdrawal and in the immediate post-withdrawal week.¹¹

Stock et al¹² randomized 26 patients who met criteria for AWS to receive gabapentin or chlordiazepoxide. Gabapentin doses were 1,200 mg/d orally for 3 days, followed by 900 mg/d, 600 mg/d, and 300 mg/d for 1 day each. Chlordiazepoxide doses were 100 mg/d orally for 3 days, followed by 75 mg/d, 50 mg/d, and 25 mg/d for 1 day each. The ESS, Penn Alcohol Craving Scale (PACS), ataxia rating, and CIWA-Ar were administered daily. Thirty-five percent of participants dropped out at the end of the 7-day treatment period. Days 1 to 4 were considered the early treatment period, and Days 5 to 7 were considered the late treatment period. The adjusted mean ESS score did not differ significantly between the randomized groups during the early stage (P = .61) vs the late stage, in which the adjusted mean ESS score was significantly lower with gabapentin compared with chlordiazepoxide (P = .04). The differences in PACS scores between the groups were not statistically significant in either stage (early stage P = .59 vs late stage P = .08), but a trend of lower PACS scores was noted with gabapentin in the later stage. No participant in either group had ataxia during the study. In both groups, CIWA-Ar scores were reduced similarly.

Conclusion: The researchers concluded that gabapentin treatment resulted in a significantly greater reduction in sedation (ESS) and a trend toward reduced alcohol craving (PACS) by the end of treatment compared with chlordiazepoxide treatment.¹²

Schacht et al¹³ analyzed functional magnetic resonance imaging data from 48 patients who were alcohol-dependent in a 6-week RCT. Patients were randomized to receive gabapentin up to 1,200 mg/d for 39 days plus flumazenil for 2 days (GP/FMZ group) or an oral placebo and placebo infusions on the same time course. Evaluations included the SCID, ADS, and Obsessive-Compulsive Drinking Scale (OCDS). On Day 1, the CIWA-Ar was administered; it was used to ensure equal distribution of individuals with higher alcohol withdrawal symptoms between medication groups. There were no significant effects of initial alcohol withdrawal symptom status or medication. However, there was a significant interaction between these factors: patients with higher alcohol withdrawal symptoms who received GP/FMZ and those with lower alcohol withdrawal symptoms who received placebo demonstrated greater cue-elicited activation, relative to the other groups, and had less subsequent drinking, which reflected differences in deactivation between alcohol and beverage stimuli, in a cluster that encompassed the dorsal ACC (dACC) (family-wise error-corrected cluster probability of P = .012; 99 voxels; local maxima at [-3, 39, 18] and [6, 33, 9]). In the GP/FMZ group, patients with higher alcohol withdrawal symptoms had significantly greater activation, while in the placebo group, patients with lower alcohol withdrawal symptoms had greater activation.

Conclusion: The researchers concluded that alterations in task-related deactivation of dACC, a component of the default mode network, may predict better alcohol treatment response, while activation of DLPFC, an area associated with selective attention, may predict relapse drinking.¹³

Continue to: Carbamazepine

Carbamazepine

The characteristics of the carbamazepine studies included in this review are summarized in Table 2.^14-19

Björkqvist et al¹⁴ randomized 105 men with AWS to placebo or carbamazepine. On initial assessment, history, physical examination, relevant labs, and intoxication assessments were recorded. On subsequent visits, nursing staff recorded withdrawal symptoms for patients as 0 to 2 (0 = no specific symptoms, 1 = patient only complained when asked about specific symptoms, 2 = patient complained of withdrawal symptoms without being asked, or if symptoms were severe or obvious to others). Along with the above, vital signs and a visual analogue scale of 0 to 10 (0 = feeling could not be worse, 10 = feeling could not be better) were recorded at each visit. The dose was weight-dependent and administered as follows: on Days 1 and 2, 1+1+2 tablets of carbamazepine, 200 mg, or placebo; Days 3 and 4, 1+1+1 tablets; and Days 5 and 6, 1+0+1 tablets. Every patient received dichloralphenazone as needed. All patients were given vitamin B 3 times a day. Most withdrawal symptoms decreased faster in the carbamazepine group on Day 2 (P = .01) and on Day 4 (P = .1). On the visual analogue scale, scores varied between patients. On Day 1, the mean score was 2.5 times higher in the carbamazepine group compared with the placebo group, and this difference increased to 3 times by Day 7 (P < .01). The patient’s estimated ability to work improved significantly faster in the carbamazepine group than in the placebo group (P < .01).

Conclusion: The authors concluded that compared with placebo, carbamazepine was able to more quickly decrease withdrawal symptoms, especially insomnia and subjective recovery.¹⁴

Ritola et al¹⁵ randomized 68 hospitalized men with AWS to carbamazepine, 200 mg/d, or clomethiazole, 300 mg/d, for 1 week. The target withdrawal symptoms included gastrointestinal and sleep disturbances; anxiety; aggressiveness; and cardiovascular, depressive, psychotic, and neurologic symptoms. A 4-point rating scale was used for individual symptoms (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom). On the day of admission (Day 0), all patients were given 50 to 100 mg of chlordiazepoxide IM and 2 tablets and 4 capsules of the trial preparations (either the tablets or capsules were active, and the others were placebos) in the evening. Five patients dropped out of the clomethiazole group and 1 from the carbamazepine group. No significant difference between the 2 treatments were found by the patient, nurse, or physician.

Conclusion: The authors concluded that carbamazepine seemed to be as effective as clomethiazole in the treatment of milder alcohol withdrawal symptoms. Final treatment results were equally good in both groups. Sleep disturbance resolved faster in the carbamazepine group.¹⁵

Continue to: Agricola et al

Agricola et al¹⁶ compared carbamazepine to tiapride for treatment of acute AWS. In this study, 60 patients were randomized to carbamazepine, 200 mg 3 times a day, or tiapride, 200 mg 3 times a day. All patients were hospitalized with severe AWS preceding DT. The patients were evaluated for withdrawal symptoms (gastrointestinal and cardiovascular symptoms, sleep disturbances, anxiety, aggression, fear, depression, psychotic symptoms, and certain neurologic symptoms). The severity of these symptoms was scored as follows: 0 = no symptoms; 1 = moderate symptoms; and 2 = severe symptoms. At each visit, an overall evaluation of the patient’s clinical condition was made according to a visual analogue scale (100 = worst condition, 0 = best condition). On Day 7, both the doctor and patient evaluated treatment efficacy according to a 4-point scale (1 = no efficacy, 4 = excellent efficacy). There was no significant difference between carbamazepine and tiapride in terms of total symptoms score and visual analogue scale assessment. Carbamazepine was found to have faster relief of symptoms and a significantly greater reduction in symptom score on Day 2 (P < .01). Carbamazepine had a preferential action on fear, nightmares, and hallucinations. The proportion of patients in whom anxiety improved after treatment was 96.2% for carbamazepine and 71.4% for tiapride (P < .05). Aggressiveness and gastrointestinal discomfort resolved faster in the tiapride group. No cases of DT were observed.

Conclusion: The researchers concluded that either carbamazepine or tiapride provides an appropriate alternative in the treatment of inpatients with severe AWS.¹⁶

Stuppaeck et al¹⁷ compared the efficacy of carbamazepine to oxazepam in 60 inpatients who had symptoms of alcohol withdrawal. Alcohol withdrawal was measured with the CIWA-A, and patients with scores >20 were enrolled in the study. The Clinical Global Impression (CGI) scale and self-rated Adjective Checklist (ACL) were also used. On Days 1 to 3, patients received oxazepam, 120 mg/d, or carbamazepine, 800 mg/d. From Day 4 to 7, doses were decreased to 90 mg/d and 600 mg/d, respectively. After the 7-day trial, all patients were treated with carbamazepine, 200 mg twice a day on Day 8 and 200 mg at night on Day 9. Two patients withdrew consent and 6 dropped out due to adverse effects. During the 7-day trial, when comparing all improvements on CIWA-A, ACL, and CGI scales, carbamazepine was equivalent to oxazepam up to Day 5, and then superior on Days 6 and 7 (P ≤ .05). No decrease in white blood cell count was found in the carbamazepine group.

Conclusion: The authors concluded that carbamazepine is as effective as oxazepam and may be a viable alternative that does not interact with alcohol or cause delirium.¹⁷

Malcolm et al¹⁸ compared the effects of carbamazepine and lorazepam in patients in an outpatient setting who had single vs multiple previous alcohol withdrawals. The study included 136 patients who satisfied DSM-IV criteria for alcohol dependence and alcohol withdrawal, with a blood alcohol level ≤0.1 g/dL, a Mini-Mental State Examination (MMSE) score ≤26, and a CIWA-Ar score ≤10 on admission. Patients also completed the ADS to quantify the severity of alcohol dependence. Daily drinking was measured by patient report using a daily drinking log and blood alcohol level. Heavy drinking was defined as ≥4 standard drinks per day for women and ≥5 drinks per day for men. On Day 1, patients were randomized to receive carbamazepine, 600 to 800 mg/d,or lorazepam, 6 to 8 mg/d, in divided doses, which was tapered to carbamazepine, 200 mg/d, or lorazepam, 2 mg/d, on Day 5. All patients received thiamine for 12 days. In the immediate post-detoxification period, carbamazepine-treated patients were less likely to relapse, and if they did drink, they drank less than those treated with lorazepam (P = .003). Even in patients who had multiple previous detoxifications, those randomized to carbamazepine drank less than those in lorazepam group (P = .004). Patients in the lorazepam group had significant higher rebound withdrawal symptoms (P = .007).

Continue to: Conclusion

Conclusion: The researchers concluded that carbamazepine and lorazepam were both effective in reducing alcohol withdrawal symptoms. They also concluded that carbamazepine was less likely to cause rebound withdrawal and more likely to reduce post-treatment drinking; among those who did drink, there was less heavy drinking.¹⁸

Malcolm et al¹⁹ conducted a 5-day double-blind RCT with 136 outpatients who met DSM-IV criteria for alcohol withdrawal. Patients were evaluated by CIWA before getting medications and then daily for 5 days. Patients were randomized to receive carbamazepine, 600 to 800 mg/d on Day 1, 200 mg 3 times a day on Day 2, 200 mg twice a day on Days 3 and 4, and 200 mg once on Day 5. Participants were randomized to receive lorazepam, 6 to 8 mg/d in divided doses on Day 1, 2 mg 3 times a day on Day 2, 2 mg twice a day on Days 3 and 4, and 2 mg once on Day 5. Ability to return to work was self-rated on a 100-mm visual analogue scale, with 0 being “totally unable to return to work’’ and 100 representing “being fully able to return to work.’’ Self-report measures of sleep quality were made using a 100-mm visual analogue scale, with 0 = “the very worst night’s sleep I’ve ever had’’ and 100 = “the very best night’s sleep I’ve ever had.’’ Carbamazepine significantly reduced anxiety (P = .0007). Visual analogue measures of sleep quality indicated a statistically significant main effect of medication on sleep that favored carbamazepine (P = .0186).

Conclusion: The authors concluded that when treating patients with mild to moderate alcohol withdrawal symptoms, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.¹⁹

Sodium valproate

The characteristics of the sodium valproate studies included in this review are summarized in Table 3.^20,21

Lambie et al²⁰ evaluated the use of sodium valproate in the treatment of AWS. A total of 49 patients were randomized to a sodium valproate group (n = 22) or a control group (n = 27). All participants were inpatients receiving treatment for alcohol use disorder and substance use disorder for 7 days. Patients in the sodium valproate group received 800 mg every 8 hours for 7 days. Patients were observed daily for occurrence of withdrawal symptoms. Nurses who were blinded to the group assignment graded the degree and severity of symptoms. The trial was initially designed so that chlormethiazole and/or tranquilizers were added to sodium valproate when withdrawal symptoms occurred. However, after treating the first few patients, it became evident that additional medications were not needed. In the treatment group, 13 participants received only sodium valproate, 4 patients needed a tranquilizer, 4 needed chlormethiazole, and 1 needed both. In the control group, 1 received only sodium valproate, 4 received a tranquilizer, 14 received chlormethiazole, and 8 needed both. One patient, who entered the study twice, had a withdrawal seizure when in control group and no seizure on second admission in the sodium valproate group. Physical symptoms disappeared quickly in the sodium valproate group (mean of 2 days vs 2.6 days in the control group). Fourteen patients in the control group received chlormethiazole, compared with only 4 patients in sodium valproate group.

Continue to: Conclusion

Conclusion: The researchers concluded that physical symptoms disappeared quicker in the sodium valproate group than in the control group.²⁰

Hillbom et al²¹ evaluated the efficacy of sodium valproate vs carbamazepine vs placebo to prevent alcohol withdrawal seizures. A total of 138 participants were studied. Forty-three were assigned to the carbamazepine group, 46 to the sodium valproate group, and 49 to the placebo group. The RCT lasted 4 days. The initial medication doses were 1,200 mg/d. Participants in the carbamazepine group experienced more adverse effects than those in the sodium valproate or placebo groups (P < .001). As a result, approximately one-half of the participants in the carbamazepine group stopped taking the medication. This finding was dependent on the dose of carbamazepine; >800 mg/d resulted in poor tolerance to adverse effects. Seizures occurred among patients in all 3 arms of the study; in the sodium valproate group, 1 participant had a seizure vs 2 participants in the carbamazepine group and 3 in the placebo group. On the other hand, DT occurred only in the sodium valproate and placebo groups.

Conclusion: Researchers concluded that when using sodium valproate or carbamazepine to prevent alcohol withdrawal seizures in an outpatient setting, the adverse effects may outweigh the benefits.²¹

Lamotrigine

The characteristics of the lamotrigine study included in this review are summarized in Table 3.²²

Djokić et al²² evaluated the efficiency of lamotrigine in the treatment of DT. A total of 240 participants who met International Classification of Diseases-10 criteria for DT were randomized to a control group that was treated with anticonvulsants according to an NIAAA protocol (2004), or to an experimental group that was treated with lamotrigine. The CIWA-Ar and the Memorial Delirium Assessment Scale (MDAS) were administered for objective assessment of clinical symptoms, superimposed medical complications, general condition of the patient, adverse effects, and mortality rate. Statistically significant differences between the experimental and control groups were apparent after the third day of therapy, when a drop in the average CIWA-Ar score was observed in the experimental group, while the control group still had high scores (P < .01). After the fifth day of treatment, the differences in scores were more apparent, with the experimental group showing CIWA-Ar scores equal to those of persons with mild/moderate DT, while those in the control group still had high scores. After the tenth day, participants in the experimental group did not have any alcohol withdrawal symptoms, while control group participants were just beginning to get out of life-threatening danger. Death occurred in 4.1% of control group participants and 3.4% of experimental group participants; this difference in mortality rate was not statistically significant.

Continue to: Conclusion

Conclusion: Researchers concluded that lamotrigine is significantly efficacious in the treatment of DT, but does not decrease the mortality rate.²²

What to know before you prescribe

AWS is a medical emergency that if left untreated leads to several complications and possibly death. Although benzodiazepines are considered the gold standard for treating AWS, the adverse effects associated with their use advocates for finding alternatives. Anticonvulsants can be an effective alternative for treating AWS. In our literature review, we found 16 double-blind RCTs that used an anticonvulsant medication for the treatment of AWS. Of these, 7 involved gabapentin, 6 involved carbamazepine, 1 involved sodium valproate, 1 involved sodium valproate vs carbamazepine, and 1 involved lamotrigine. Overall, the use of anticonvulsants resulted in significant improvement of mild to moderate symptoms of AWS.

There were more studies of carbamazepine and gabapentin than of other anticonvulsants. All the anticonvulsants offered potential benefits. They decreased the probability of a withdrawal seizure and other complications and effectively reduced alcohol cravings. Anticonvulsants were useful for preventing rebound withdrawal symptoms and reducing post-treatment alcohol consumption, especially in patients who had multiple previous withdrawals. Anticonvulsants were particularly helpful for patients with mood disorders such as depression. In the studies we reviewed, anticonvulsants caused less sedation compared with benzodiazepines, and also decreased the occurrence of relapse.

Dosing recommendations. In the studies included in our review, gabapentin was effective at a dosage of 1,600 mg/d (given as 400 mg 4 times a day). This was tapered as follows: 400 mg 4 times a day on Days 1 to 3, 400 mg 3 times a day on Day 4, 400 mg twice a day on Day 5, and 400 mg once a day on Day 6. Carbamazepine was effective at 600 to 800 mg/d, and was tapered by decreasing by 200 mg as follows: 800 mg/d on Days 1 to 3, 600 mg/d on Day 4, 400 mg on Day 5, and 200 mg/d on Day 6. In the reviewed study, the maximum dose of lamotrigine never exceeded 200 mg/d and was administered for 28 days; the exact dosing and taper plan were not described. The dosing of sodium valproate ranged from 1,200 mg/d to 1600 mg/d for 7 days, followed by decreasing by 200 mg each day. The recommended duration of treatment varied; on average for all anticonvulsants, it was 7 to 12 days, followed by a taper. Carbamazepine was shown to be superior to oxazepam in ameliorating the symptoms of AWS.

Adverse effects. When considering the tolerability, adverse effect profile, duration of action, and effectiveness of the anticonvulsants included in our review, gabapentin appears to be the safest agent to choose. For the other anticonvulsants, the risks might outweigh the benefits. Specifically, in a comparison of sodium valproate and carbamazepine, Hillbom et al²¹ concluded that in doses >800 mg/d, carbamazepine has potential to cause more adverse effects than benefits. However, Agricola et al¹⁶ found that carbamazepine had a preferential action on fear, nightmares, and hallucinations.

Continue to: A few caveats

Our review focused a large collection of data from multiple databases and RCTs only. However, its limitations include:

• there was no measure of heterogeneity
• the studies had short treatment duration
• most studies evaluated predominantly male participants
• some studies were underpowered.

Our review laid a groundwork for future research that includes more well-designed RCTs and/or meta-analyses of recent studies that evaluated the use anticonvulsants for treating AWS.

Bottom Line

Evidence suggests certain anticonvulsants may be an effective alternative to benzodiazepines for the treatment of mild to moderate alcohol withdrawal syndrome. Gabapentin may be the safest anticonvulsant to prescribe. Other anticonvulsants to consider include carbamazepine, sodium valproate, and lamotrigine, but for these agents, the risks might outweigh the benefits.

Related Resources

• Myrick H, Anton RF. Treatment of alcohol withdrawal. Alcohol Health Res World. 1998;22(1):38-43. https://pubs.niaaa.nih.gov/publications/arh22-1/38-43.pdf
• World Health Organization. Management of alcohol withdrawal. Published 2012. https://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/

Drug Brand Names

Carbamazepine • Tegretol
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Lorazepam • Ativan
Oxcarbazepine • Trileptal
Phenytoin • Dilantin
Sodium valproate • Depakote

Acknowledgments

The authors thank Geetha Manikkara, MD, Madhuri Jakkam Setty, MD, and Elizabeth DeOreo, MD, for their efforts with the systematic review research.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

We would like to describe the case of a patient we treated who developed neuropsychiatric symptoms secondary to recreational use of nitrous oxide (N₂O).

Mr. N, a 24-year-old military veteran, presented to the emergency department (ED) with symptoms of numbness, tingling of his entire body, and difficulty walking for the past 3 days. His family recently became concerned when they noted changes in his personality and behavior, including increased irritability, verbal aggression, and paranoia. The family reported that before the recent changes, Mr. N had typically been calm and had a pleasant temperament. When Mr. N’s symptoms progressed to difficulty ambulating, his family brought him to the ED for evaluation.

During his interview, Mr. N reported that he started using N₂O 2 years ago for recreational purposes because he learned it is legal to purchase and undetectable on a urine drug screen. He said he had been using >100 N₂O canisters per day and had spent approximately $15,000 over the past few months. His use had increasingly escalated up to 3 days before his visit to the ED, which was the last day he used N₂O.

Mr. N was admitted to the inpatient medical service. Laboratory testing revealed a low-normal vitamin B12 level of 254 pg/mL (normal range: 200 to 900 pg/mL), an elevated methylmalonic acid blood level of 2,491 nmol/L (normal range: 73 to 376 nmol/L), and an elevated homocysteine blood level of 22.4 μmol/L (normal range: 0 to 15 μmol/L). Magnetic resonance imaging studies showed hyperintensity regions on his cervical spine from the C1 to C6 levels. These changes suggested demyelination due to vitamin B12 deficiency from N₂O abuse.

Mr. N was started on vitamin B12 injections and physical therapy, which led to the resolution of his concerning neurologic symptoms. A few weeks after admission, he was discharged with outpatient follow-up services. Unfortunately, he was lost to follow-up.

Approximately 1 year later, Mr. N returned to the ED with anxiety and paranoid ideation. Medical workup at the time was normal (including vitamin B12 and methylmalonic acid blood levels). He denied any recent substance use and was admitted voluntarily to the psychiatric unit. He declined the recommended treatment of risperidone. Because he showed no signs or symptoms that warranted involuntary retention, he was discharged. Over the next few months, he had 4 visits to the ED with similar concerns and poor adherence to outpatient treatment.

On Mr. N’s fourth admission, he agreed to a course of long-acting injectable paliperidone and escitalopram to target his psychotic and anxious symptoms. These treatments stabilized him, and he was discharged. Neuropsychological testing later showed impairment across several cognitive domains, including memory, processing speed, attention, and executive functioning.

Continue to: Identifying N₂O use

Identifying N₂O use. N₂O is not detected on routine drug screen panels. Obtaining a careful psychiatric and substance use history, as well as conducting a neurologic assessment, are helpful to identify N₂O use. Both acute and chronic inhalation of N₂O can result in vitamin B12 deficiency with hematologic (megaloblastic anemia), neurologic (subacute combined degeneration of spinal cord, motor-sensory polyneuropathy), and psychiatric sequelae (memory loss, depression, hypomania, transient psychosis).¹ Patients who exhibit these changes warrant workup for vitamin B12 deficiency, which includes testing for B12, homocysteine, and methylmalonic acid blood levels. Magnetic resonance imaging should be considered for patients who exhibit neurologic symptoms.

The means by which N₂O causes neuropsychiatric changes have been explored in the literature. There is general consensus that part of N₂O’s deleterious effects is due to the inactivation of vitamin B12 by the irreversible oxidation of Cob(I)alamin to Cob(III)alamin.¹

Treatment. The recommended treatment is high-dose oral or parenteral vitamin B12.¹ Repletion of vitamin B12 is believed to reverse the course of illness. However, our patient’s symptoms of paranoia and delusions persisted despite resolution of his neurologic symptoms after the underlying vitamin B12 deficiency was corrected.

Due to N₂O’s wide availability and growing recreational use, it is important for clinicians to ask their patients about their use of this substance. The abuse of N₂O remains an important topic that requires further research, particularly in adolescents, who are still undergoing significant brain development.^2,3

Daniel Roberts, MD, MSW
PGY-3 Psychiatric Resident
Department of Psychiatry
New York University Grossman School of Medicine
New York, New York

Pantea Farahmand, MA, MD
Assistant Professor
Department of Psychiatry
New York University Grossman School of Medicine
Inpatient Psychiatrist
Veterans Administration New York Harbor Healthcare System
New York, New York

Adam Wolkin, MD
Associate Professor and Vice Chair
New York University Grossman School of Medicine
Associate Chief of Staff for Mental Health
Veterans Administration New York Harbor Healthcare System
New York, New York

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

Naltrexone reduces the risk for hospitalization for alcohol use disorder (AUD), regardless of whether it is used alone or in conjunction with disulfiram or acamprosate, research suggests.

Katarzyna Bialasiewicz/Thinkstock

Investigators analyzed 10-year data on more than 125,000 Swedish residents with AUD and found that naltrexone, used as monotherapy or combined with acamprosate or disulfiram, was associated with significantly lower risk for AUD hospitalization or all-cause hospitalization in comparison with patients who did not use AUD medication. The patients ranged in age from 16 to 64 years.

By contrast, benzodiazepines and acamprosate monotherapy were associated with increased risk for AUD hospitalization.

“The take-home message for practicing clinicians would be that especially naltrexone use is associated with favorable treatment outcomes and should be utilized as part of the treatment protocol for AUD,” study investigator Milja Heikkinen, MD, specialist in forensic psychiatry and addiction medicine, University of Eastern Finland, Kuopio, told this news organization.

On the other hand, “benzodiazepines should be avoided and should not be administered other than for alcohol withdrawal symptoms,” she said.

The study was published online Jan. 4 in Addiction.
 

Real-world data

Previous research has shown that disulfiram, acamprosate, naltrexone, and nalmefene are efficacious in treating AUD, but most studies have been randomized controlled trials or meta-analyses, the authors write.

“Very little is known about overall health outcomes (such as risks of hospitalization and mortality) associated with specific treatments in real-world circumstances,” they write.

“The study was motivated by the fact that, although AUD is a significant public health concern, very little is known, especially about the comparative effectiveness of medications indicated in AUD,” said Dr. Heikkinen.

To investigate, the researchers drew on data from several large nationwide Swedish registers that encompassed 125,556 patients who had been diagnosed with AUD (62.5% men; mean [standard deviation] age, 38.1 [15.9] years). They followed the cohort over a median of 4.6 years (interquartile range, 2.1-.2 years).

During the follow-up period, roughly one-fourth of patients (25.6) underwent treatment with one or more drugs.

AUD pharmacotherapy ‘underutilized’

Close to one-fourth of patients (23.9%) experienced the main outcome event (AUD-related hospitalization) during the follow-up period.

The within-individual analysis showed that naltrexone – whether used as monotherapy or adjunctively with disulfiram or acamprosate – “was associated with a significantly lower risk of AUD-related hospitalization, compared to those time periods in which the same individual did not use any AUD medication,” the authors report.

By contrast, they state, acamprosate monotherapy and benzodiazepines were associated with a significantly higher risk for AUD-related hospitalization.

‘Ravages’ of benzodiazepines

Commenting on the study in an interview, John Krystal, MD, professor and chair of psychiatry and director of the Center for the Translational Neuroscience of Alcoholism, Yale University, New Haven, Conn., said, “The main message from the study for practicing clinicians is that treatment works.”

Dr. Krystal, who was not involved with the study, noted that “many practicing clinicians are discouraged by the course of their patients with AUD, and this study highlights that naltrexone, perhaps in combination with other medications, may be effective in preventing hospitalization and, presumably, other hospitalization-related complications of AUD.”

Also commenting on the study, Raymond Anton, MD, professor, department of psychiatry and behavioral sciences, Medical University of South Carolina, Charleston, suggested that the “clinical knowledge of the harm of benzodiazepines in those with AUD is reinforced by these findings.”

In fact, the harm of benzodiazepines might be the study’s “most important message ... [a message that was] recently highlighted by the Netflix series “The Queen’s Gambit”, which shows the ravages of using both together, or how one leads to potential addiction with the other,” said Dr. Anton, who was not involved with the study.

The other “big take-home message is that naltrexone should be used more frequently,” said Dr. Anton, distinguished professor of psychiatry at the university and scientific director of the Charleston Alcohol Research Center. He noted that there are “recent data suggesting some clinical and genetic indicators that predict responsiveness to these medications, improving efficacy.”

The study was funded by the Finnish Ministry of Social Affairs and Health. Dr. Heikkinen reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Krystal consults for companies currently developing other treatments for AUDs and receives medications to test from AstraZeneca and Novartis for NIAAA-funded research programs. Dr. Anton has consulted for Alkermes, Lipha, and Lundbeck in the past. He is also chair of the Alcohol Clinical Trials Initiative, which is a public-private partnership partially sponsored by several companies and has received grant funding from the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism to study pharmacotherapies, including naltrexone, nalmefene, and acamprosate.

A version of this article first appeared on Medscape.com.

Naltrexone reduces the risk for hospitalization for alcohol use disorder (AUD), regardless of whether it is used alone or in conjunction with disulfiram or acamprosate, research suggests.

Katarzyna Bialasiewicz/Thinkstock

Investigators analyzed 10-year data on more than 125,000 Swedish residents with AUD and found that naltrexone, used as monotherapy or combined with acamprosate or disulfiram, was associated with significantly lower risk for AUD hospitalization or all-cause hospitalization in comparison with patients who did not use AUD medication. The patients ranged in age from 16 to 64 years.

By contrast, benzodiazepines and acamprosate monotherapy were associated with increased risk for AUD hospitalization.

“The take-home message for practicing clinicians would be that especially naltrexone use is associated with favorable treatment outcomes and should be utilized as part of the treatment protocol for AUD,” study investigator Milja Heikkinen, MD, specialist in forensic psychiatry and addiction medicine, University of Eastern Finland, Kuopio, told this news organization.

On the other hand, “benzodiazepines should be avoided and should not be administered other than for alcohol withdrawal symptoms,” she said.

The study was published online Jan. 4 in Addiction.
 

Real-world data

Previous research has shown that disulfiram, acamprosate, naltrexone, and nalmefene are efficacious in treating AUD, but most studies have been randomized controlled trials or meta-analyses, the authors write.

“Very little is known about overall health outcomes (such as risks of hospitalization and mortality) associated with specific treatments in real-world circumstances,” they write.

“The study was motivated by the fact that, although AUD is a significant public health concern, very little is known, especially about the comparative effectiveness of medications indicated in AUD,” said Dr. Heikkinen.

To investigate, the researchers drew on data from several large nationwide Swedish registers that encompassed 125,556 patients who had been diagnosed with AUD (62.5% men; mean [standard deviation] age, 38.1 [15.9] years). They followed the cohort over a median of 4.6 years (interquartile range, 2.1-.2 years).

During the follow-up period, roughly one-fourth of patients (25.6) underwent treatment with one or more drugs.

AUD pharmacotherapy ‘underutilized’

Close to one-fourth of patients (23.9%) experienced the main outcome event (AUD-related hospitalization) during the follow-up period.

The within-individual analysis showed that naltrexone – whether used as monotherapy or adjunctively with disulfiram or acamprosate – “was associated with a significantly lower risk of AUD-related hospitalization, compared to those time periods in which the same individual did not use any AUD medication,” the authors report.

By contrast, they state, acamprosate monotherapy and benzodiazepines were associated with a significantly higher risk for AUD-related hospitalization.

‘Ravages’ of benzodiazepines

Commenting on the study in an interview, John Krystal, MD, professor and chair of psychiatry and director of the Center for the Translational Neuroscience of Alcoholism, Yale University, New Haven, Conn., said, “The main message from the study for practicing clinicians is that treatment works.”

Dr. Krystal, who was not involved with the study, noted that “many practicing clinicians are discouraged by the course of their patients with AUD, and this study highlights that naltrexone, perhaps in combination with other medications, may be effective in preventing hospitalization and, presumably, other hospitalization-related complications of AUD.”

Also commenting on the study, Raymond Anton, MD, professor, department of psychiatry and behavioral sciences, Medical University of South Carolina, Charleston, suggested that the “clinical knowledge of the harm of benzodiazepines in those with AUD is reinforced by these findings.”

In fact, the harm of benzodiazepines might be the study’s “most important message ... [a message that was] recently highlighted by the Netflix series “The Queen’s Gambit”, which shows the ravages of using both together, or how one leads to potential addiction with the other,” said Dr. Anton, who was not involved with the study.

The other “big take-home message is that naltrexone should be used more frequently,” said Dr. Anton, distinguished professor of psychiatry at the university and scientific director of the Charleston Alcohol Research Center. He noted that there are “recent data suggesting some clinical and genetic indicators that predict responsiveness to these medications, improving efficacy.”

The study was funded by the Finnish Ministry of Social Affairs and Health. Dr. Heikkinen reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Krystal consults for companies currently developing other treatments for AUDs and receives medications to test from AstraZeneca and Novartis for NIAAA-funded research programs. Dr. Anton has consulted for Alkermes, Lipha, and Lundbeck in the past. He is also chair of the Alcohol Clinical Trials Initiative, which is a public-private partnership partially sponsored by several companies and has received grant funding from the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism to study pharmacotherapies, including naltrexone, nalmefene, and acamprosate.

A version of this article first appeared on Medscape.com.

Naltrexone reduces the risk for hospitalization for alcohol use disorder (AUD), regardless of whether it is used alone or in conjunction with disulfiram or acamprosate, research suggests.

Katarzyna Bialasiewicz/Thinkstock

Investigators analyzed 10-year data on more than 125,000 Swedish residents with AUD and found that naltrexone, used as monotherapy or combined with acamprosate or disulfiram, was associated with significantly lower risk for AUD hospitalization or all-cause hospitalization in comparison with patients who did not use AUD medication. The patients ranged in age from 16 to 64 years.

By contrast, benzodiazepines and acamprosate monotherapy were associated with increased risk for AUD hospitalization.

“The take-home message for practicing clinicians would be that especially naltrexone use is associated with favorable treatment outcomes and should be utilized as part of the treatment protocol for AUD,” study investigator Milja Heikkinen, MD, specialist in forensic psychiatry and addiction medicine, University of Eastern Finland, Kuopio, told this news organization.

On the other hand, “benzodiazepines should be avoided and should not be administered other than for alcohol withdrawal symptoms,” she said.

The study was published online Jan. 4 in Addiction.
 

Real-world data

Previous research has shown that disulfiram, acamprosate, naltrexone, and nalmefene are efficacious in treating AUD, but most studies have been randomized controlled trials or meta-analyses, the authors write.

“Very little is known about overall health outcomes (such as risks of hospitalization and mortality) associated with specific treatments in real-world circumstances,” they write.

“The study was motivated by the fact that, although AUD is a significant public health concern, very little is known, especially about the comparative effectiveness of medications indicated in AUD,” said Dr. Heikkinen.

To investigate, the researchers drew on data from several large nationwide Swedish registers that encompassed 125,556 patients who had been diagnosed with AUD (62.5% men; mean [standard deviation] age, 38.1 [15.9] years). They followed the cohort over a median of 4.6 years (interquartile range, 2.1-.2 years).

During the follow-up period, roughly one-fourth of patients (25.6) underwent treatment with one or more drugs.

AUD pharmacotherapy ‘underutilized’

Close to one-fourth of patients (23.9%) experienced the main outcome event (AUD-related hospitalization) during the follow-up period.

The within-individual analysis showed that naltrexone – whether used as monotherapy or adjunctively with disulfiram or acamprosate – “was associated with a significantly lower risk of AUD-related hospitalization, compared to those time periods in which the same individual did not use any AUD medication,” the authors report.

By contrast, they state, acamprosate monotherapy and benzodiazepines were associated with a significantly higher risk for AUD-related hospitalization.

‘Ravages’ of benzodiazepines

Commenting on the study in an interview, John Krystal, MD, professor and chair of psychiatry and director of the Center for the Translational Neuroscience of Alcoholism, Yale University, New Haven, Conn., said, “The main message from the study for practicing clinicians is that treatment works.”

Dr. Krystal, who was not involved with the study, noted that “many practicing clinicians are discouraged by the course of their patients with AUD, and this study highlights that naltrexone, perhaps in combination with other medications, may be effective in preventing hospitalization and, presumably, other hospitalization-related complications of AUD.”

Also commenting on the study, Raymond Anton, MD, professor, department of psychiatry and behavioral sciences, Medical University of South Carolina, Charleston, suggested that the “clinical knowledge of the harm of benzodiazepines in those with AUD is reinforced by these findings.”

In fact, the harm of benzodiazepines might be the study’s “most important message ... [a message that was] recently highlighted by the Netflix series “The Queen’s Gambit”, which shows the ravages of using both together, or how one leads to potential addiction with the other,” said Dr. Anton, who was not involved with the study.

The other “big take-home message is that naltrexone should be used more frequently,” said Dr. Anton, distinguished professor of psychiatry at the university and scientific director of the Charleston Alcohol Research Center. He noted that there are “recent data suggesting some clinical and genetic indicators that predict responsiveness to these medications, improving efficacy.”

The study was funded by the Finnish Ministry of Social Affairs and Health. Dr. Heikkinen reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Krystal consults for companies currently developing other treatments for AUDs and receives medications to test from AstraZeneca and Novartis for NIAAA-funded research programs. Dr. Anton has consulted for Alkermes, Lipha, and Lundbeck in the past. He is also chair of the Alcohol Clinical Trials Initiative, which is a public-private partnership partially sponsored by several companies and has received grant funding from the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism to study pharmacotherapies, including naltrexone, nalmefene, and acamprosate.

A version of this article first appeared on Medscape.com.

The national rate of methamphetamine overdose deaths shot up significantly between 2011 and 2018, particularly among non-Hispanic American Indian and Alaska Native communities, new research shows.

Rates rose for both men and women but more so among men, the study found. The spike in these deaths underscores the need for culturally tailored prevention and treatment strategies, the study authors said.

“While much attention is focused on the opioid crisis, a methamphetamine crisis has been quietly, but actively, gaining steam – particularly among American Indians and Alaska Natives, who are disproportionately affected by a number of health conditions,” senior investigator Nora D. Volkow, MD, director of the National Institute on Drug Abuse, said in a press release.

The study was published online Jan. 20 in JAMA Psychiatry.
 

Highly toxic

Methamphetamine is highly toxic. Its use is associated with pulmonary and cardiovascular pathology and frequently co-occurs with other substance use and mental disorders.

In addition, there are currently no Food and Drug Administration–approved medications to reverse methamphetamine overdose or treat methamphetamine use disorder.

However, behavioral therapies can be effective in reducing the harm associated with methamphetamine use. In addition, a recent clinical trial reported significant therapeutic benefits with the combination of naltrexone with bupropion in patients with methamphetamine use disorder.

For the study, the investigators used deidentified public health surveillance data from the Centers for Disease Control and Prevention’s National Vital Statistics System files for multiple causes of death.

The researchers used the psychostimulant category to estimate death rates from methamphetamine. The authors noted that up to 90% of psychostimulant-involved death certificates mentioned methamphetamine.

Researchers stratified age-adjusted overdose death rates during 2011-2018 by sex and race/ethnicity and limited the analysis to those aged 25-54 years. Approximately 80% of methamphetamine users are between the ages of 25 and 54 years.

During the study period, rates for methamphetamine-involved deaths increased from 1.8 to 10.1 per 100,000 among men (average annual percentage change, 29.1; 95% confidence interval, 25.5-32.8; P < .001) and from 0.8 to 4.5 per 100,000 among women (AAPC, 28.1; 95% CI, 25.1-31.2; P < .001).
 

Need for tailored interventions

For both men and women, those in non-Hispanic American Indian or Alaska Native communities had the highest rates. These increased from 5.6 to 26.4 per 100,000 among men and from 3.6 to 15.6 per 100,000 among women.

While American Indian and Alaska Native individuals experience sociostructural disadvantages, their cultural strengths “can be leveraged to improve addiction outcomes,” the investigators wrote.

Non-Hispanic Whites had the second highest rates. These rose from 2.2 to 12.6 per 100,000 among men (AAPC, 29.8; 95% CI, 24.3-35.4; P < .001) and from 1.1 to 6.2 per 100,000 among women (AAPC, 29.1; 95% CI, 25.2-33.2; P < .001).

Rates among Hispanic individuals increased from 1.4 to 6.6 per 100,000 for men and from 0.5 to 2.0 per 100,000 for women. Among non-Hispanic Asian individuals, rates increased to 3.4 per 100,000 for men and to 1.1 per 100,000 for women. Non-Hispanic Black individuals had low rates. Within each racial/ethnic group, rates were higher among men versus women.

Methamphetamine death rates may be underestimated because some overdose death certificates do not report specific drugs involved, the authors noted.

Identifying populations that have a higher rate of methamphetamine overdose is a crucial step toward curbing the underlying methamphetamine crisis,” study author Beth Han, MD, PhD, of NIDA, said in a press release.

“By focusing on the unique needs of individuals and developing culturally tailored interventions, we can begin to move away from one-size-fits-all approaches and toward more effective, tailored interventions,” she said.

The study was sponsored by NIDA.

A version of this article first appeared on Medscape.com.

The national rate of methamphetamine overdose deaths shot up significantly between 2011 and 2018, particularly among non-Hispanic American Indian and Alaska Native communities, new research shows.

Rates rose for both men and women but more so among men, the study found. The spike in these deaths underscores the need for culturally tailored prevention and treatment strategies, the study authors said.

“While much attention is focused on the opioid crisis, a methamphetamine crisis has been quietly, but actively, gaining steam – particularly among American Indians and Alaska Natives, who are disproportionately affected by a number of health conditions,” senior investigator Nora D. Volkow, MD, director of the National Institute on Drug Abuse, said in a press release.

The study was published online Jan. 20 in JAMA Psychiatry.
 

Highly toxic

Methamphetamine is highly toxic. Its use is associated with pulmonary and cardiovascular pathology and frequently co-occurs with other substance use and mental disorders.

In addition, there are currently no Food and Drug Administration–approved medications to reverse methamphetamine overdose or treat methamphetamine use disorder.

However, behavioral therapies can be effective in reducing the harm associated with methamphetamine use. In addition, a recent clinical trial reported significant therapeutic benefits with the combination of naltrexone with bupropion in patients with methamphetamine use disorder.

For the study, the investigators used deidentified public health surveillance data from the Centers for Disease Control and Prevention’s National Vital Statistics System files for multiple causes of death.

The researchers used the psychostimulant category to estimate death rates from methamphetamine. The authors noted that up to 90% of psychostimulant-involved death certificates mentioned methamphetamine.

Researchers stratified age-adjusted overdose death rates during 2011-2018 by sex and race/ethnicity and limited the analysis to those aged 25-54 years. Approximately 80% of methamphetamine users are between the ages of 25 and 54 years.

During the study period, rates for methamphetamine-involved deaths increased from 1.8 to 10.1 per 100,000 among men (average annual percentage change, 29.1; 95% confidence interval, 25.5-32.8; P < .001) and from 0.8 to 4.5 per 100,000 among women (AAPC, 28.1; 95% CI, 25.1-31.2; P < .001).
 

Need for tailored interventions

For both men and women, those in non-Hispanic American Indian or Alaska Native communities had the highest rates. These increased from 5.6 to 26.4 per 100,000 among men and from 3.6 to 15.6 per 100,000 among women.

While American Indian and Alaska Native individuals experience sociostructural disadvantages, their cultural strengths “can be leveraged to improve addiction outcomes,” the investigators wrote.

Non-Hispanic Whites had the second highest rates. These rose from 2.2 to 12.6 per 100,000 among men (AAPC, 29.8; 95% CI, 24.3-35.4; P < .001) and from 1.1 to 6.2 per 100,000 among women (AAPC, 29.1; 95% CI, 25.2-33.2; P < .001).

Rates among Hispanic individuals increased from 1.4 to 6.6 per 100,000 for men and from 0.5 to 2.0 per 100,000 for women. Among non-Hispanic Asian individuals, rates increased to 3.4 per 100,000 for men and to 1.1 per 100,000 for women. Non-Hispanic Black individuals had low rates. Within each racial/ethnic group, rates were higher among men versus women.

Methamphetamine death rates may be underestimated because some overdose death certificates do not report specific drugs involved, the authors noted.

Identifying populations that have a higher rate of methamphetamine overdose is a crucial step toward curbing the underlying methamphetamine crisis,” study author Beth Han, MD, PhD, of NIDA, said in a press release.

“By focusing on the unique needs of individuals and developing culturally tailored interventions, we can begin to move away from one-size-fits-all approaches and toward more effective, tailored interventions,” she said.

The study was sponsored by NIDA.

A version of this article first appeared on Medscape.com.

The national rate of methamphetamine overdose deaths shot up significantly between 2011 and 2018, particularly among non-Hispanic American Indian and Alaska Native communities, new research shows.

Rates rose for both men and women but more so among men, the study found. The spike in these deaths underscores the need for culturally tailored prevention and treatment strategies, the study authors said.

“While much attention is focused on the opioid crisis, a methamphetamine crisis has been quietly, but actively, gaining steam – particularly among American Indians and Alaska Natives, who are disproportionately affected by a number of health conditions,” senior investigator Nora D. Volkow, MD, director of the National Institute on Drug Abuse, said in a press release.

The study was published online Jan. 20 in JAMA Psychiatry.
 

Highly toxic

Methamphetamine is highly toxic. Its use is associated with pulmonary and cardiovascular pathology and frequently co-occurs with other substance use and mental disorders.

In addition, there are currently no Food and Drug Administration–approved medications to reverse methamphetamine overdose or treat methamphetamine use disorder.

However, behavioral therapies can be effective in reducing the harm associated with methamphetamine use. In addition, a recent clinical trial reported significant therapeutic benefits with the combination of naltrexone with bupropion in patients with methamphetamine use disorder.

For the study, the investigators used deidentified public health surveillance data from the Centers for Disease Control and Prevention’s National Vital Statistics System files for multiple causes of death.

The researchers used the psychostimulant category to estimate death rates from methamphetamine. The authors noted that up to 90% of psychostimulant-involved death certificates mentioned methamphetamine.

Researchers stratified age-adjusted overdose death rates during 2011-2018 by sex and race/ethnicity and limited the analysis to those aged 25-54 years. Approximately 80% of methamphetamine users are between the ages of 25 and 54 years.

During the study period, rates for methamphetamine-involved deaths increased from 1.8 to 10.1 per 100,000 among men (average annual percentage change, 29.1; 95% confidence interval, 25.5-32.8; P < .001) and from 0.8 to 4.5 per 100,000 among women (AAPC, 28.1; 95% CI, 25.1-31.2; P < .001).
 

Need for tailored interventions

For both men and women, those in non-Hispanic American Indian or Alaska Native communities had the highest rates. These increased from 5.6 to 26.4 per 100,000 among men and from 3.6 to 15.6 per 100,000 among women.

While American Indian and Alaska Native individuals experience sociostructural disadvantages, their cultural strengths “can be leveraged to improve addiction outcomes,” the investigators wrote.

Non-Hispanic Whites had the second highest rates. These rose from 2.2 to 12.6 per 100,000 among men (AAPC, 29.8; 95% CI, 24.3-35.4; P < .001) and from 1.1 to 6.2 per 100,000 among women (AAPC, 29.1; 95% CI, 25.2-33.2; P < .001).

Rates among Hispanic individuals increased from 1.4 to 6.6 per 100,000 for men and from 0.5 to 2.0 per 100,000 for women. Among non-Hispanic Asian individuals, rates increased to 3.4 per 100,000 for men and to 1.1 per 100,000 for women. Non-Hispanic Black individuals had low rates. Within each racial/ethnic group, rates were higher among men versus women.

Methamphetamine death rates may be underestimated because some overdose death certificates do not report specific drugs involved, the authors noted.

Identifying populations that have a higher rate of methamphetamine overdose is a crucial step toward curbing the underlying methamphetamine crisis,” study author Beth Han, MD, PhD, of NIDA, said in a press release.

“By focusing on the unique needs of individuals and developing culturally tailored interventions, we can begin to move away from one-size-fits-all approaches and toward more effective, tailored interventions,” she said.

The study was sponsored by NIDA.

A version of this article first appeared on Medscape.com.

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

After bariatric surgery, patients have a “much higher” risk of unhealthy alcohol use—even if they had no documented unhealthy drinking at baseline, according to researchers from the Durham Veteran Affairs (VA) Medical Center in North Carolina.

Based on their findings, the researchers estimate that for every 21 patients who undergo laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB), on average one from each group will develop unhealthy alcohol use.

The researchers collected electronic health record (EHR) data from 2,608 veterans who underwent LSG or RYGB at any bariatric center in the VA health system between 2008 and 2016, and compared that group with a nonsurgical control group.

Nearly all the patients screened negative for unhealthy alcohol use in the 2-year baseline period; however, their mean AUDIT-C scores and the probability of unhealthy alcohol use both increased significantly 3 to 8 years after surgery when compared with the control group. Eight years after an LSG, the probability was 3.4% higher (7.9% vs 4.5%). Eight years after an RYGB, the probability was 9.2% vs 4.4%, a difference of 4.8%.

The estimated prevalence of unhealthy alcohol use 8 years after bariatric surgery was higher for patients with unhealthy drinking at baseline (30  40%) than it was for those without baseline unhealthy drinking (5 - 10%). However, the probability was significantly higher for patients who had an RYGB than it was for nonsurgical control patients after 8 years, which might reflect alcohol pharmacokinetics changes, the researchers say.

Not drinking alcohol is the safest option after bariatric surgery, the researchers say, given that blood alcohol concentration peaks at higher levels after the operation. They advise monitoring patients long-term, using the three-item AUDIT-C scale. And, importantly, they advise cautioning patients undergoing bariatric surgery that drinking alcohol can escalate, even if they have had no history of drinking above recommended limits.

After bariatric surgery, patients have a “much higher” risk of unhealthy alcohol use—even if they had no documented unhealthy drinking at baseline, according to researchers from the Durham Veteran Affairs (VA) Medical Center in North Carolina.

Based on their findings, the researchers estimate that for every 21 patients who undergo laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB), on average one from each group will develop unhealthy alcohol use.

The researchers collected electronic health record (EHR) data from 2,608 veterans who underwent LSG or RYGB at any bariatric center in the VA health system between 2008 and 2016, and compared that group with a nonsurgical control group.

Nearly all the patients screened negative for unhealthy alcohol use in the 2-year baseline period; however, their mean AUDIT-C scores and the probability of unhealthy alcohol use both increased significantly 3 to 8 years after surgery when compared with the control group. Eight years after an LSG, the probability was 3.4% higher (7.9% vs 4.5%). Eight years after an RYGB, the probability was 9.2% vs 4.4%, a difference of 4.8%.

The estimated prevalence of unhealthy alcohol use 8 years after bariatric surgery was higher for patients with unhealthy drinking at baseline (30  40%) than it was for those without baseline unhealthy drinking (5 - 10%). However, the probability was significantly higher for patients who had an RYGB than it was for nonsurgical control patients after 8 years, which might reflect alcohol pharmacokinetics changes, the researchers say.

Not drinking alcohol is the safest option after bariatric surgery, the researchers say, given that blood alcohol concentration peaks at higher levels after the operation. They advise monitoring patients long-term, using the three-item AUDIT-C scale. And, importantly, they advise cautioning patients undergoing bariatric surgery that drinking alcohol can escalate, even if they have had no history of drinking above recommended limits.

After bariatric surgery, patients have a “much higher” risk of unhealthy alcohol use—even if they had no documented unhealthy drinking at baseline, according to researchers from the Durham Veteran Affairs (VA) Medical Center in North Carolina.

Based on their findings, the researchers estimate that for every 21 patients who undergo laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB), on average one from each group will develop unhealthy alcohol use.

The researchers collected electronic health record (EHR) data from 2,608 veterans who underwent LSG or RYGB at any bariatric center in the VA health system between 2008 and 2016, and compared that group with a nonsurgical control group.

Nearly all the patients screened negative for unhealthy alcohol use in the 2-year baseline period; however, their mean AUDIT-C scores and the probability of unhealthy alcohol use both increased significantly 3 to 8 years after surgery when compared with the control group. Eight years after an LSG, the probability was 3.4% higher (7.9% vs 4.5%). Eight years after an RYGB, the probability was 9.2% vs 4.4%, a difference of 4.8%.

The estimated prevalence of unhealthy alcohol use 8 years after bariatric surgery was higher for patients with unhealthy drinking at baseline (30  40%) than it was for those without baseline unhealthy drinking (5 - 10%). However, the probability was significantly higher for patients who had an RYGB than it was for nonsurgical control patients after 8 years, which might reflect alcohol pharmacokinetics changes, the researchers say.

Not drinking alcohol is the safest option after bariatric surgery, the researchers say, given that blood alcohol concentration peaks at higher levels after the operation. They advise monitoring patients long-term, using the three-item AUDIT-C scale. And, importantly, they advise cautioning patients undergoing bariatric surgery that drinking alcohol can escalate, even if they have had no history of drinking above recommended limits.

Federal officials on Thursday announced a plan to largely drop the so-called X-waiver requirement for buprenorphine prescriptions for physicians in a bid to remove an administrative procedure widely seen as a barrier to opioid use disorder (OUD) treatment.

The Department of Health & Human Services unveiled new practice guidelines that include an exemption from current certification requirements. The exemption applies to physicians already registered with the Drug Enforcement Administration.

A restriction included in the new HHS policy is a limit of treating no more than 30 patients with buprenorphine for OUD at any one time. There is an exception to this limit for hospital-based physicians, such as those working in emergency departments, HHS said.

The policy change applies only to the prescription of drugs or formulations covered under the so-called X-waiver of the Controlled Substance Act, such as buprenorphine, and does not apply to methadone. The new guidelines say the date on which they will take effect will be added after publication in the Federal Register. HHS did not immediately answer a request from this news organization for a more specific timeline.
 

Welcomed change

The change in prescribing rule was widely welcomed, with the American Medical Association issuing a statement endorsing the revision. The AMA and many prescribers and researchers had seen the X-waiver as a hurdle to address the nation’s opioid epidemic.

There were more than 83,000 deaths attributed to drug overdoses in the United States in the 12 months ending in June 2020. This is the highest number of overdose deaths ever recorded in a 12-month period, HHS said in a press release, which cited data from the Centers for Disease Control and Prevention.

In a tweet about the new policy, Peter Grinspoon, MD, a Boston internist and author of the memoir “Free Refills: A Doctor Confronts His Addiction,” contrasted the relative ease with which clinicians can give medicines that carry a risk for abuse with the challenge that has existed in trying to provide patients with buprenorphine.

“Absolutely insane that we need a special waiver for buprenorphine to TREAT opioid addiction, but not to prescribe oxycodone, Vicodin, etc., which can get people in trouble in the first place!!” Dr. Grinspoon tweeted.

Patrice Harris, MD, chair of the AMA’s Opioid Task Force and the organization’s immediate past president, said removing the X-waiver requirement can help lessen the stigma associated with this OUD treatment. The AMA had urged HHS to change the regulation.

“With this change, office-based physicians and physician-led teams working with patients to manage their other medical conditions can also treat them for their opioid use disorder without being subjected to a separate and burdensome regulatory regime,” Dr. Harris said in the AMA statement.

Researchers have in recent years sought to highlight what they described as missed opportunities for OUD treatment because of the need for the X-waiver. 

Buprenorphine is a cost-effective treatment for opioid use disorder, which reduces the risk of injection-related infections and mortality risk, notes a study published online last month in JAMA Network Open.  

However, results showed that fewer than 2% of obstetrician-gynecologists who examined women enrolled in Medicaid were trained to prescribe buprenorphine. The study, which was based on data from 31, 211 ob.gyns. who accepted Medicaid insurance, was created to quantify how many were on the list of Drug Addiction Treatment Act buprenorphine-waived clinicians.

The Drug Addiction Treatment Act has required 8 hours of training for physicians and 24 hours for nurse practitioners and physician assistants for the X-waiver needed to prescribe buprenorphine, the investigators report.
 

‘X the X-waiver’

Only 10% of recent family residency graduates reported being adequately trained to prescribe buprenorphine and only 7% reported actually prescribing the drug, write Kevin Fiscella, MD, University of Rochester (N.Y.) Medical Center and colleagues in a 2018 Viewpoint article published in JAMA Psychiatry.

In the article, which was subtitled “X the X Waiver,” they called for deregulation of buprenorphine as a way of mainstreaming treatment for OUD.

“The DATA 2000 has failed – too few physicians have obtained X-waivers,” the authors write. “Regulations reinforce the stigma surrounding buprenorphine prescribers and patients who receive it while constraining access and discouraging patient engagement and retention in treatment.”

The change, announced Jan. 14, leaves in place restrictions on prescribing for clinicians other than physicians. On a call with reporters, Adm. Brett P. Giroir, MD, assistant secretary for health, suggested that federal officials should take further steps to remove hurdles to buprenorphine prescriptions.

“Many people will say this has gone too far,” Dr. Giroir said of the drive to end the X-waiver for clinicians. “But I believe more people will say this has not gone far enough.”

A version of this article first appeared on Medscape.com.

Federal officials on Thursday announced a plan to largely drop the so-called X-waiver requirement for buprenorphine prescriptions for physicians in a bid to remove an administrative procedure widely seen as a barrier to opioid use disorder (OUD) treatment.

The Department of Health & Human Services unveiled new practice guidelines that include an exemption from current certification requirements. The exemption applies to physicians already registered with the Drug Enforcement Administration.

A restriction included in the new HHS policy is a limit of treating no more than 30 patients with buprenorphine for OUD at any one time. There is an exception to this limit for hospital-based physicians, such as those working in emergency departments, HHS said.

The policy change applies only to the prescription of drugs or formulations covered under the so-called X-waiver of the Controlled Substance Act, such as buprenorphine, and does not apply to methadone. The new guidelines say the date on which they will take effect will be added after publication in the Federal Register. HHS did not immediately answer a request from this news organization for a more specific timeline.
 

Welcomed change

The change in prescribing rule was widely welcomed, with the American Medical Association issuing a statement endorsing the revision. The AMA and many prescribers and researchers had seen the X-waiver as a hurdle to address the nation’s opioid epidemic.

There were more than 83,000 deaths attributed to drug overdoses in the United States in the 12 months ending in June 2020. This is the highest number of overdose deaths ever recorded in a 12-month period, HHS said in a press release, which cited data from the Centers for Disease Control and Prevention.

In a tweet about the new policy, Peter Grinspoon, MD, a Boston internist and author of the memoir “Free Refills: A Doctor Confronts His Addiction,” contrasted the relative ease with which clinicians can give medicines that carry a risk for abuse with the challenge that has existed in trying to provide patients with buprenorphine.

“Absolutely insane that we need a special waiver for buprenorphine to TREAT opioid addiction, but not to prescribe oxycodone, Vicodin, etc., which can get people in trouble in the first place!!” Dr. Grinspoon tweeted.

Patrice Harris, MD, chair of the AMA’s Opioid Task Force and the organization’s immediate past president, said removing the X-waiver requirement can help lessen the stigma associated with this OUD treatment. The AMA had urged HHS to change the regulation.

“With this change, office-based physicians and physician-led teams working with patients to manage their other medical conditions can also treat them for their opioid use disorder without being subjected to a separate and burdensome regulatory regime,” Dr. Harris said in the AMA statement.

Researchers have in recent years sought to highlight what they described as missed opportunities for OUD treatment because of the need for the X-waiver. 

Buprenorphine is a cost-effective treatment for opioid use disorder, which reduces the risk of injection-related infections and mortality risk, notes a study published online last month in JAMA Network Open.  

However, results showed that fewer than 2% of obstetrician-gynecologists who examined women enrolled in Medicaid were trained to prescribe buprenorphine. The study, which was based on data from 31, 211 ob.gyns. who accepted Medicaid insurance, was created to quantify how many were on the list of Drug Addiction Treatment Act buprenorphine-waived clinicians.

The Drug Addiction Treatment Act has required 8 hours of training for physicians and 24 hours for nurse practitioners and physician assistants for the X-waiver needed to prescribe buprenorphine, the investigators report.
 

‘X the X-waiver’

Only 10% of recent family residency graduates reported being adequately trained to prescribe buprenorphine and only 7% reported actually prescribing the drug, write Kevin Fiscella, MD, University of Rochester (N.Y.) Medical Center and colleagues in a 2018 Viewpoint article published in JAMA Psychiatry.

In the article, which was subtitled “X the X Waiver,” they called for deregulation of buprenorphine as a way of mainstreaming treatment for OUD.

“The DATA 2000 has failed – too few physicians have obtained X-waivers,” the authors write. “Regulations reinforce the stigma surrounding buprenorphine prescribers and patients who receive it while constraining access and discouraging patient engagement and retention in treatment.”

The change, announced Jan. 14, leaves in place restrictions on prescribing for clinicians other than physicians. On a call with reporters, Adm. Brett P. Giroir, MD, assistant secretary for health, suggested that federal officials should take further steps to remove hurdles to buprenorphine prescriptions.

“Many people will say this has gone too far,” Dr. Giroir said of the drive to end the X-waiver for clinicians. “But I believe more people will say this has not gone far enough.”

A version of this article first appeared on Medscape.com.

Federal officials on Thursday announced a plan to largely drop the so-called X-waiver requirement for buprenorphine prescriptions for physicians in a bid to remove an administrative procedure widely seen as a barrier to opioid use disorder (OUD) treatment.

The Department of Health & Human Services unveiled new practice guidelines that include an exemption from current certification requirements. The exemption applies to physicians already registered with the Drug Enforcement Administration.

A restriction included in the new HHS policy is a limit of treating no more than 30 patients with buprenorphine for OUD at any one time. There is an exception to this limit for hospital-based physicians, such as those working in emergency departments, HHS said.

The policy change applies only to the prescription of drugs or formulations covered under the so-called X-waiver of the Controlled Substance Act, such as buprenorphine, and does not apply to methadone. The new guidelines say the date on which they will take effect will be added after publication in the Federal Register. HHS did not immediately answer a request from this news organization for a more specific timeline.
 

Welcomed change

The change in prescribing rule was widely welcomed, with the American Medical Association issuing a statement endorsing the revision. The AMA and many prescribers and researchers had seen the X-waiver as a hurdle to address the nation’s opioid epidemic.

There were more than 83,000 deaths attributed to drug overdoses in the United States in the 12 months ending in June 2020. This is the highest number of overdose deaths ever recorded in a 12-month period, HHS said in a press release, which cited data from the Centers for Disease Control and Prevention.

In a tweet about the new policy, Peter Grinspoon, MD, a Boston internist and author of the memoir “Free Refills: A Doctor Confronts His Addiction,” contrasted the relative ease with which clinicians can give medicines that carry a risk for abuse with the challenge that has existed in trying to provide patients with buprenorphine.

“Absolutely insane that we need a special waiver for buprenorphine to TREAT opioid addiction, but not to prescribe oxycodone, Vicodin, etc., which can get people in trouble in the first place!!” Dr. Grinspoon tweeted.

Patrice Harris, MD, chair of the AMA’s Opioid Task Force and the organization’s immediate past president, said removing the X-waiver requirement can help lessen the stigma associated with this OUD treatment. The AMA had urged HHS to change the regulation.

“With this change, office-based physicians and physician-led teams working with patients to manage their other medical conditions can also treat them for their opioid use disorder without being subjected to a separate and burdensome regulatory regime,” Dr. Harris said in the AMA statement.

Researchers have in recent years sought to highlight what they described as missed opportunities for OUD treatment because of the need for the X-waiver. 

Buprenorphine is a cost-effective treatment for opioid use disorder, which reduces the risk of injection-related infections and mortality risk, notes a study published online last month in JAMA Network Open.  

However, results showed that fewer than 2% of obstetrician-gynecologists who examined women enrolled in Medicaid were trained to prescribe buprenorphine. The study, which was based on data from 31, 211 ob.gyns. who accepted Medicaid insurance, was created to quantify how many were on the list of Drug Addiction Treatment Act buprenorphine-waived clinicians.

The Drug Addiction Treatment Act has required 8 hours of training for physicians and 24 hours for nurse practitioners and physician assistants for the X-waiver needed to prescribe buprenorphine, the investigators report.
 

‘X the X-waiver’

Only 10% of recent family residency graduates reported being adequately trained to prescribe buprenorphine and only 7% reported actually prescribing the drug, write Kevin Fiscella, MD, University of Rochester (N.Y.) Medical Center and colleagues in a 2018 Viewpoint article published in JAMA Psychiatry.

In the article, which was subtitled “X the X Waiver,” they called for deregulation of buprenorphine as a way of mainstreaming treatment for OUD.

“The DATA 2000 has failed – too few physicians have obtained X-waivers,” the authors write. “Regulations reinforce the stigma surrounding buprenorphine prescribers and patients who receive it while constraining access and discouraging patient engagement and retention in treatment.”

The change, announced Jan. 14, leaves in place restrictions on prescribing for clinicians other than physicians. On a call with reporters, Adm. Brett P. Giroir, MD, assistant secretary for health, suggested that federal officials should take further steps to remove hurdles to buprenorphine prescriptions.

“Many people will say this has gone too far,” Dr. Giroir said of the drive to end the X-waiver for clinicians. “But I believe more people will say this has not gone far enough.”

A version of this article first appeared on Medscape.com.

Depression and tobacco use in childhood significantly increased the risk for opioid use in young adults, according to data from a prospective study of approximately 1,000 individuals.

Previous research, including the annual Monitoring the Future study, documents opioid use among adolescents in the United States, but childhood risk factors for opioid use in young adults have not been well studied, wrote Lilly Shanahan, PhD, of the University of Zürich, and colleagues.

In a prospective cohort study published in JAMA Pediatrics, the researchers identified 1,252 non-Hispanic White and American Indian opioid-naive individuals aged 9-16 years in rural North Carolina. They interviewed participants and parents up to 7 times between January 1993 and December 2000, and interviewed participants only at ages 19, 21, 25, and 30 years between January 1999 and December 2015.

Overall, 24.2% of study participants had used a nonheroin opioid by age 30 years, and both chronic depression and dysthymia were significantly associated with this use (odds ratios 5.43 and 7.13, respectively).

In addition, 155 participants (8.8%) reported weekly use of a nonheroin opioid, and 95 (6.6%) reported weekly heroin use by age 30 years. Chronic depression and dysthymia also were strongly associated with weekly nonheroin opioid use (OR 8.89 and 11.51, respectively).

In a multivariate analysis, depression, tobacco use, and cannabis use at ages 9-16 years were strongly associated with overall opioid use at ages 19-30 years.

“One possible reason childhood chronic depression increases the risk of later opioid use is self-medication, including the use of psychoactive substances, to alleviate depression,” the researchers noted. In addition, the mood-altering properties of opioids may increase their appeal to depressed youth as a way to relieve impaired reward system function, they said.

Potential mechanisms for the association between early tobacco use and later opioid use include the alterations to neurodevelopment caused by nicotine exposure in adolescence, as well as increased risk for depression, reduced pain thresholds, and use of nicotine as a gateway to harder drugs, the researchers added.

Several childhood risk factors were not associated with young adult opioid use in multivariate analysis in this study, including alcohol use, sociodemographic status, maltreatment, family dysfunction, and anxiety, the researchers wrote. “Previous studies typically measured these risk factors retrospectively or in late adolescence and young adulthood, and most did not consider depressive disorders, which may mediate associations between select childhood risk factors and later opioid use,” they said.

The study findings were limited by several factors, including the inability to distinguish between medical and nonmedical opioid use, the incomplete list of available opioids, and the exclusion of Black participants because of low sample size, the researchers noted. However, the results were strengthened by the longitudinal, community-representative design and the inclusion of up to 11 assessments of opioid use, they said.

“Our findings suggest strong opportunities for early prevention and intervention, including in primary care settings,” using known evidence-based strategies, they concluded.
 

More screening is needed

“Children in the United States are at high risk of serious adult health issues as a result of childhood factors such as ACEs (adverse childhood experiences),” said Suzanne C. Boulter, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H. “This study looks prospectively at other factors in childhood over a long period of time leading to opioid usage, with its serious risks and health consequences including overdose death,” she said. “It is unclear what the effects of COVID-19 will be on the population of children growing up now and how opioid usage might change as a result,” she noted.

“Some of the links to adult usage are predictable, such as depression, tobacco use, and cannabis use in early adolescence,” said Dr. Boulter. “Surprising was the lack of correlation between anxiety, early alcohol use, child mistreatment, and sociodemographic factors with future opioid use,” she said.

The take-home message for clinicians is to screen children and adolescents for factors leading to opioid usage in young adults “with preventive strategies including avoidance of pain medication prescriptions and early referral and treatment for depression and use of cannabis and tobacco products using tools like SBIRT (Screening, Brief Intervention, and Referral to Treatment),” Dr. Boulter emphasized.

As for additional research, “It would be interesting to study e-cigarette usage and see if the correlation with future opioid usage is similar to older tobacco products,” she said. “Also helpful would be to delve deeper into connections between medical or dental diagnoses when opioids were first prescribed and later usage of those products,” Dr. Boulter noted.

The study was supported in part by the by the National Institute of Mental Health and the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Boulter had no disclosures but serves on the Pediatric News Editorial Advisory Board.

Depression and tobacco use in childhood significantly increased the risk for opioid use in young adults, according to data from a prospective study of approximately 1,000 individuals.

Previous research, including the annual Monitoring the Future study, documents opioid use among adolescents in the United States, but childhood risk factors for opioid use in young adults have not been well studied, wrote Lilly Shanahan, PhD, of the University of Zürich, and colleagues.

In a prospective cohort study published in JAMA Pediatrics, the researchers identified 1,252 non-Hispanic White and American Indian opioid-naive individuals aged 9-16 years in rural North Carolina. They interviewed participants and parents up to 7 times between January 1993 and December 2000, and interviewed participants only at ages 19, 21, 25, and 30 years between January 1999 and December 2015.

Overall, 24.2% of study participants had used a nonheroin opioid by age 30 years, and both chronic depression and dysthymia were significantly associated with this use (odds ratios 5.43 and 7.13, respectively).

In addition, 155 participants (8.8%) reported weekly use of a nonheroin opioid, and 95 (6.6%) reported weekly heroin use by age 30 years. Chronic depression and dysthymia also were strongly associated with weekly nonheroin opioid use (OR 8.89 and 11.51, respectively).

In a multivariate analysis, depression, tobacco use, and cannabis use at ages 9-16 years were strongly associated with overall opioid use at ages 19-30 years.

“One possible reason childhood chronic depression increases the risk of later opioid use is self-medication, including the use of psychoactive substances, to alleviate depression,” the researchers noted. In addition, the mood-altering properties of opioids may increase their appeal to depressed youth as a way to relieve impaired reward system function, they said.

Potential mechanisms for the association between early tobacco use and later opioid use include the alterations to neurodevelopment caused by nicotine exposure in adolescence, as well as increased risk for depression, reduced pain thresholds, and use of nicotine as a gateway to harder drugs, the researchers added.

Several childhood risk factors were not associated with young adult opioid use in multivariate analysis in this study, including alcohol use, sociodemographic status, maltreatment, family dysfunction, and anxiety, the researchers wrote. “Previous studies typically measured these risk factors retrospectively or in late adolescence and young adulthood, and most did not consider depressive disorders, which may mediate associations between select childhood risk factors and later opioid use,” they said.

The study findings were limited by several factors, including the inability to distinguish between medical and nonmedical opioid use, the incomplete list of available opioids, and the exclusion of Black participants because of low sample size, the researchers noted. However, the results were strengthened by the longitudinal, community-representative design and the inclusion of up to 11 assessments of opioid use, they said.

“Our findings suggest strong opportunities for early prevention and intervention, including in primary care settings,” using known evidence-based strategies, they concluded.
 

More screening is needed

“Children in the United States are at high risk of serious adult health issues as a result of childhood factors such as ACEs (adverse childhood experiences),” said Suzanne C. Boulter, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H. “This study looks prospectively at other factors in childhood over a long period of time leading to opioid usage, with its serious risks and health consequences including overdose death,” she said. “It is unclear what the effects of COVID-19 will be on the population of children growing up now and how opioid usage might change as a result,” she noted.

“Some of the links to adult usage are predictable, such as depression, tobacco use, and cannabis use in early adolescence,” said Dr. Boulter. “Surprising was the lack of correlation between anxiety, early alcohol use, child mistreatment, and sociodemographic factors with future opioid use,” she said.

The take-home message for clinicians is to screen children and adolescents for factors leading to opioid usage in young adults “with preventive strategies including avoidance of pain medication prescriptions and early referral and treatment for depression and use of cannabis and tobacco products using tools like SBIRT (Screening, Brief Intervention, and Referral to Treatment),” Dr. Boulter emphasized.

As for additional research, “It would be interesting to study e-cigarette usage and see if the correlation with future opioid usage is similar to older tobacco products,” she said. “Also helpful would be to delve deeper into connections between medical or dental diagnoses when opioids were first prescribed and later usage of those products,” Dr. Boulter noted.

The study was supported in part by the by the National Institute of Mental Health and the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Boulter had no disclosures but serves on the Pediatric News Editorial Advisory Board.

Depression and tobacco use in childhood significantly increased the risk for opioid use in young adults, according to data from a prospective study of approximately 1,000 individuals.

Previous research, including the annual Monitoring the Future study, documents opioid use among adolescents in the United States, but childhood risk factors for opioid use in young adults have not been well studied, wrote Lilly Shanahan, PhD, of the University of Zürich, and colleagues.

In a prospective cohort study published in JAMA Pediatrics, the researchers identified 1,252 non-Hispanic White and American Indian opioid-naive individuals aged 9-16 years in rural North Carolina. They interviewed participants and parents up to 7 times between January 1993 and December 2000, and interviewed participants only at ages 19, 21, 25, and 30 years between January 1999 and December 2015.

Overall, 24.2% of study participants had used a nonheroin opioid by age 30 years, and both chronic depression and dysthymia were significantly associated with this use (odds ratios 5.43 and 7.13, respectively).

In addition, 155 participants (8.8%) reported weekly use of a nonheroin opioid, and 95 (6.6%) reported weekly heroin use by age 30 years. Chronic depression and dysthymia also were strongly associated with weekly nonheroin opioid use (OR 8.89 and 11.51, respectively).

In a multivariate analysis, depression, tobacco use, and cannabis use at ages 9-16 years were strongly associated with overall opioid use at ages 19-30 years.

“One possible reason childhood chronic depression increases the risk of later opioid use is self-medication, including the use of psychoactive substances, to alleviate depression,” the researchers noted. In addition, the mood-altering properties of opioids may increase their appeal to depressed youth as a way to relieve impaired reward system function, they said.

Potential mechanisms for the association between early tobacco use and later opioid use include the alterations to neurodevelopment caused by nicotine exposure in adolescence, as well as increased risk for depression, reduced pain thresholds, and use of nicotine as a gateway to harder drugs, the researchers added.

Several childhood risk factors were not associated with young adult opioid use in multivariate analysis in this study, including alcohol use, sociodemographic status, maltreatment, family dysfunction, and anxiety, the researchers wrote. “Previous studies typically measured these risk factors retrospectively or in late adolescence and young adulthood, and most did not consider depressive disorders, which may mediate associations between select childhood risk factors and later opioid use,” they said.

The study findings were limited by several factors, including the inability to distinguish between medical and nonmedical opioid use, the incomplete list of available opioids, and the exclusion of Black participants because of low sample size, the researchers noted. However, the results were strengthened by the longitudinal, community-representative design and the inclusion of up to 11 assessments of opioid use, they said.

“Our findings suggest strong opportunities for early prevention and intervention, including in primary care settings,” using known evidence-based strategies, they concluded.
 

More screening is needed

“Children in the United States are at high risk of serious adult health issues as a result of childhood factors such as ACEs (adverse childhood experiences),” said Suzanne C. Boulter, MD, of the Geisel School of Medicine at Dartmouth, Hanover, N.H. “This study looks prospectively at other factors in childhood over a long period of time leading to opioid usage, with its serious risks and health consequences including overdose death,” she said. “It is unclear what the effects of COVID-19 will be on the population of children growing up now and how opioid usage might change as a result,” she noted.

“Some of the links to adult usage are predictable, such as depression, tobacco use, and cannabis use in early adolescence,” said Dr. Boulter. “Surprising was the lack of correlation between anxiety, early alcohol use, child mistreatment, and sociodemographic factors with future opioid use,” she said.

The take-home message for clinicians is to screen children and adolescents for factors leading to opioid usage in young adults “with preventive strategies including avoidance of pain medication prescriptions and early referral and treatment for depression and use of cannabis and tobacco products using tools like SBIRT (Screening, Brief Intervention, and Referral to Treatment),” Dr. Boulter emphasized.

As for additional research, “It would be interesting to study e-cigarette usage and see if the correlation with future opioid usage is similar to older tobacco products,” she said. “Also helpful would be to delve deeper into connections between medical or dental diagnoses when opioids were first prescribed and later usage of those products,” Dr. Boulter noted.

The study was supported in part by the by the National Institute of Mental Health and the National Institute on Drug Abuse. The researchers had no financial conflicts to disclose. Dr. Boulter had no disclosures but serves on the Pediatric News Editorial Advisory Board.

A history of suicidal behaviors or ideation, functional impairment related to mental health disorders, and socioeconomic disadvantage are the three most important risk factors predicting subsequent suicide attempts, new research suggests.

Investigators applied a machine-learning model to data on over 34,500 adults drawn from a large national survey database. After analyzing more than 2,500 survey questions, key areas were identified that yielded the most accurate predictions of who might be at risk for later suicide attempt.

‘Rich’ dataset

Previous research using machine learning approaches to study nonfatal suicide attempt prediction has focused on high-risk patients in clinical treatment. However, more than one-third of individuals making nonfatal suicide attempts do not receive mental health treatment, Mr. Garcia de la Garza noted.

To gain further insight into predictors of suicide risk in nonclinical populations, the researchers turned to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a longitudinal survey of noninstitutionalized U.S. adults.

“We wanted to extend our understanding of suicide attempt risk factors beyond high-risk clinical populations to the general adult population; and the richness of the NESARC dataset provides a unique opportunity to do so,” Mr. Garcia de la Garza said.

The NESARC surveys were conducted in two waves: Wave 1 (2001-2002) and wave 2 (2004-2005), in which participants self-reported nonfatal suicide attempts in the preceding 3 years since wave 1.

Assessment of wave 1 participants was based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV.

“This survey’s extensive assessment instrument contained a detailed evaluation of substance use, psychiatric disorders, and symptoms not routinely available in electronic health records,” Mr. Garcia de la Garza noted.

The wave 1 survey contained 2,805 separate questions. From participants’ responses, the investigators derived 180 variables for three categories: past-year, prior-to-past-year, and lifetime mental disorders.

They then identified 2,978 factors associated with suicide attempts and used a statistical method called balanced random forest to classify suicide attempts at wave 2. Each variable was accorded an “importance score” using identified wave 1 features.

The outcome variable of attempted suicide at any point during the 3 years prior to the wave 2 interview was defined by combining responses to three wave 2 questions:

• In your entire life, did you ever attempt suicide?
• If yes, how old were you the first time?
• If the most recent event occurred within the last 3 years, how old were you during the most recent time?

Suicide risk severity was classified into four groups (low, medium, high, and very high) on the basis of the top-performing risk factors.

A statistical model combining survey design and nonresponse weights enabled estimates to be representative of the U.S. population, based on the 2000 census.

Out-of-fold model prediction assessed performance of the model, using area under receiver operator curve (AUC), sensitivity, and specificity.
 

Daily functioning

Of all participants, 70.2% (n = 34,653; almost 60% women) completed wave 2 interviews. The weighted mean ages at waves 1 and 2 were 45.1 and 48.2 years, respectively.

Of wave 2 respondents, 0.6% (n = 222) attempted suicide during the preceding 3 years.

Half of those who attempted suicide within the first year were classified as “very high risk,” while 33.2% of those who attempted suicide between the first and second year and 33.3% of those who attempted suicide between the second and third year were classified as “very high risk.”

Among participants who attempted suicide between the third year and follow-up, 16.48% were classified as “very high risk.”

The model accurately captured classification of participants, even across demographic characteristics, such as age, sex, race, and income.

Younger individuals (aged 18-36 years) were at higher risk, compared with older individuals. In addition, women were at higher risk than were men, White participants were at higher risk than were non-White participants, and individuals with lower income were at greater risk than were those with higher income.

The model found that 1.8% of the U.S. population had a 10% or greater risk of a suicide attempt.

The most important risk factors identified were the three questions about previous suicidal ideation or behavior; three items from the 12-Item Short Form Health Survey (feeling downhearted, doing activities less carefully, or accomplishing less because of emotional problems); younger age; lower educational achievement; and recent financial crisis.

“The clinical assessment of suicide risk typically focuses on acute suicidal symptoms, together with depression, anxiety, substance misuse, and recent stressful events,” coinvestigator Mark Olfson, MD, PhD, professor of epidemiology, Columbia University Irving Medical Center, New York, said in an interview.

“The new findings suggest that these assessments should also consider emotional problems that interfere with daily functioning,” Dr. Olfson said.
 

Extra vigilance

Commenting on the study in an interview, April C. Foreman, PhD, an executive board member of the American Association of Suicidology, noted that some of the findings were not surprising.

“When discharging a patient from inpatient care, or seeing them in primary care, bring up mental health concerns proactively and ask whether they have ever attempted suicide or harmed themselves – even a long time ago – just as you ask about a family history of heart disease or cancer, or other health issues,” said Dr. Foreman, chief medical officer of the Kevin and Margaret Hines Foundation.

She noted that half of people who die by suicide have a primary care visit within the preceding month.

“Primary care is a great place to get a suicide history and follow the patient with extra vigilance, just as you would with any other risk factors,” Dr. Foreman said.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism and its Intramural Program. The study authors and Dr. Foreman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A history of suicidal behaviors or ideation, functional impairment related to mental health disorders, and socioeconomic disadvantage are the three most important risk factors predicting subsequent suicide attempts, new research suggests.

Investigators applied a machine-learning model to data on over 34,500 adults drawn from a large national survey database. After analyzing more than 2,500 survey questions, key areas were identified that yielded the most accurate predictions of who might be at risk for later suicide attempt.

‘Rich’ dataset

Previous research using machine learning approaches to study nonfatal suicide attempt prediction has focused on high-risk patients in clinical treatment. However, more than one-third of individuals making nonfatal suicide attempts do not receive mental health treatment, Mr. Garcia de la Garza noted.

To gain further insight into predictors of suicide risk in nonclinical populations, the researchers turned to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a longitudinal survey of noninstitutionalized U.S. adults.

“We wanted to extend our understanding of suicide attempt risk factors beyond high-risk clinical populations to the general adult population; and the richness of the NESARC dataset provides a unique opportunity to do so,” Mr. Garcia de la Garza said.

The NESARC surveys were conducted in two waves: Wave 1 (2001-2002) and wave 2 (2004-2005), in which participants self-reported nonfatal suicide attempts in the preceding 3 years since wave 1.

Assessment of wave 1 participants was based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV.

“This survey’s extensive assessment instrument contained a detailed evaluation of substance use, psychiatric disorders, and symptoms not routinely available in electronic health records,” Mr. Garcia de la Garza noted.

The wave 1 survey contained 2,805 separate questions. From participants’ responses, the investigators derived 180 variables for three categories: past-year, prior-to-past-year, and lifetime mental disorders.

They then identified 2,978 factors associated with suicide attempts and used a statistical method called balanced random forest to classify suicide attempts at wave 2. Each variable was accorded an “importance score” using identified wave 1 features.

The outcome variable of attempted suicide at any point during the 3 years prior to the wave 2 interview was defined by combining responses to three wave 2 questions:

• In your entire life, did you ever attempt suicide?
• If yes, how old were you the first time?
• If the most recent event occurred within the last 3 years, how old were you during the most recent time?

Suicide risk severity was classified into four groups (low, medium, high, and very high) on the basis of the top-performing risk factors.

A statistical model combining survey design and nonresponse weights enabled estimates to be representative of the U.S. population, based on the 2000 census.

Out-of-fold model prediction assessed performance of the model, using area under receiver operator curve (AUC), sensitivity, and specificity.
 

Daily functioning

Of all participants, 70.2% (n = 34,653; almost 60% women) completed wave 2 interviews. The weighted mean ages at waves 1 and 2 were 45.1 and 48.2 years, respectively.

Of wave 2 respondents, 0.6% (n = 222) attempted suicide during the preceding 3 years.

Half of those who attempted suicide within the first year were classified as “very high risk,” while 33.2% of those who attempted suicide between the first and second year and 33.3% of those who attempted suicide between the second and third year were classified as “very high risk.”

Among participants who attempted suicide between the third year and follow-up, 16.48% were classified as “very high risk.”

The model accurately captured classification of participants, even across demographic characteristics, such as age, sex, race, and income.

Younger individuals (aged 18-36 years) were at higher risk, compared with older individuals. In addition, women were at higher risk than were men, White participants were at higher risk than were non-White participants, and individuals with lower income were at greater risk than were those with higher income.

The model found that 1.8% of the U.S. population had a 10% or greater risk of a suicide attempt.

The most important risk factors identified were the three questions about previous suicidal ideation or behavior; three items from the 12-Item Short Form Health Survey (feeling downhearted, doing activities less carefully, or accomplishing less because of emotional problems); younger age; lower educational achievement; and recent financial crisis.

“The clinical assessment of suicide risk typically focuses on acute suicidal symptoms, together with depression, anxiety, substance misuse, and recent stressful events,” coinvestigator Mark Olfson, MD, PhD, professor of epidemiology, Columbia University Irving Medical Center, New York, said in an interview.

“The new findings suggest that these assessments should also consider emotional problems that interfere with daily functioning,” Dr. Olfson said.
 

Extra vigilance

Commenting on the study in an interview, April C. Foreman, PhD, an executive board member of the American Association of Suicidology, noted that some of the findings were not surprising.

“When discharging a patient from inpatient care, or seeing them in primary care, bring up mental health concerns proactively and ask whether they have ever attempted suicide or harmed themselves – even a long time ago – just as you ask about a family history of heart disease or cancer, or other health issues,” said Dr. Foreman, chief medical officer of the Kevin and Margaret Hines Foundation.

She noted that half of people who die by suicide have a primary care visit within the preceding month.

“Primary care is a great place to get a suicide history and follow the patient with extra vigilance, just as you would with any other risk factors,” Dr. Foreman said.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism and its Intramural Program. The study authors and Dr. Foreman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A history of suicidal behaviors or ideation, functional impairment related to mental health disorders, and socioeconomic disadvantage are the three most important risk factors predicting subsequent suicide attempts, new research suggests.

Investigators applied a machine-learning model to data on over 34,500 adults drawn from a large national survey database. After analyzing more than 2,500 survey questions, key areas were identified that yielded the most accurate predictions of who might be at risk for later suicide attempt.

‘Rich’ dataset

Previous research using machine learning approaches to study nonfatal suicide attempt prediction has focused on high-risk patients in clinical treatment. However, more than one-third of individuals making nonfatal suicide attempts do not receive mental health treatment, Mr. Garcia de la Garza noted.

To gain further insight into predictors of suicide risk in nonclinical populations, the researchers turned to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a longitudinal survey of noninstitutionalized U.S. adults.

“We wanted to extend our understanding of suicide attempt risk factors beyond high-risk clinical populations to the general adult population; and the richness of the NESARC dataset provides a unique opportunity to do so,” Mr. Garcia de la Garza said.

The NESARC surveys were conducted in two waves: Wave 1 (2001-2002) and wave 2 (2004-2005), in which participants self-reported nonfatal suicide attempts in the preceding 3 years since wave 1.

Assessment of wave 1 participants was based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV.

“This survey’s extensive assessment instrument contained a detailed evaluation of substance use, psychiatric disorders, and symptoms not routinely available in electronic health records,” Mr. Garcia de la Garza noted.

The wave 1 survey contained 2,805 separate questions. From participants’ responses, the investigators derived 180 variables for three categories: past-year, prior-to-past-year, and lifetime mental disorders.

They then identified 2,978 factors associated with suicide attempts and used a statistical method called balanced random forest to classify suicide attempts at wave 2. Each variable was accorded an “importance score” using identified wave 1 features.

The outcome variable of attempted suicide at any point during the 3 years prior to the wave 2 interview was defined by combining responses to three wave 2 questions:

• In your entire life, did you ever attempt suicide?
• If yes, how old were you the first time?
• If the most recent event occurred within the last 3 years, how old were you during the most recent time?

Suicide risk severity was classified into four groups (low, medium, high, and very high) on the basis of the top-performing risk factors.

A statistical model combining survey design and nonresponse weights enabled estimates to be representative of the U.S. population, based on the 2000 census.

Out-of-fold model prediction assessed performance of the model, using area under receiver operator curve (AUC), sensitivity, and specificity.
 

Daily functioning

Of all participants, 70.2% (n = 34,653; almost 60% women) completed wave 2 interviews. The weighted mean ages at waves 1 and 2 were 45.1 and 48.2 years, respectively.

Of wave 2 respondents, 0.6% (n = 222) attempted suicide during the preceding 3 years.

Half of those who attempted suicide within the first year were classified as “very high risk,” while 33.2% of those who attempted suicide between the first and second year and 33.3% of those who attempted suicide between the second and third year were classified as “very high risk.”

Among participants who attempted suicide between the third year and follow-up, 16.48% were classified as “very high risk.”

The model accurately captured classification of participants, even across demographic characteristics, such as age, sex, race, and income.

Younger individuals (aged 18-36 years) were at higher risk, compared with older individuals. In addition, women were at higher risk than were men, White participants were at higher risk than were non-White participants, and individuals with lower income were at greater risk than were those with higher income.

The model found that 1.8% of the U.S. population had a 10% or greater risk of a suicide attempt.

The most important risk factors identified were the three questions about previous suicidal ideation or behavior; three items from the 12-Item Short Form Health Survey (feeling downhearted, doing activities less carefully, or accomplishing less because of emotional problems); younger age; lower educational achievement; and recent financial crisis.

“The clinical assessment of suicide risk typically focuses on acute suicidal symptoms, together with depression, anxiety, substance misuse, and recent stressful events,” coinvestigator Mark Olfson, MD, PhD, professor of epidemiology, Columbia University Irving Medical Center, New York, said in an interview.

“The new findings suggest that these assessments should also consider emotional problems that interfere with daily functioning,” Dr. Olfson said.
 

Extra vigilance

Commenting on the study in an interview, April C. Foreman, PhD, an executive board member of the American Association of Suicidology, noted that some of the findings were not surprising.

“When discharging a patient from inpatient care, or seeing them in primary care, bring up mental health concerns proactively and ask whether they have ever attempted suicide or harmed themselves – even a long time ago – just as you ask about a family history of heart disease or cancer, or other health issues,” said Dr. Foreman, chief medical officer of the Kevin and Margaret Hines Foundation.

She noted that half of people who die by suicide have a primary care visit within the preceding month.

“Primary care is a great place to get a suicide history and follow the patient with extra vigilance, just as you would with any other risk factors,” Dr. Foreman said.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism and its Intramural Program. The study authors and Dr. Foreman have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.