Pain

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

In the late 1980s and early 1990s, an emphasis on better pain management led health care professionals (HCPs) to increase prescribing of opioids to better manage patient’s pain. In 1991, 76 million prescriptions were written for opioids in the United States, and by 2011, the number had nearly tripled to 219 million.¹ Overdose rates increased as well, nearly tripling from 1999 to 2014.² Of the 52,404 US deaths from drug overdoses in the in 2015, 63% involved an opioid.²

Opioid Safety Initiative

In response to the growing opioid epidemic, the US Department of Veterans Affairs (VA) created the Opioid Safety Initiative in 2014.³ This comprehensive, multifaceted initiative was designed to improve the care and safety of veterans managed with opioid therapy and promote rational opioid prescribing and monitoring. In 2016 the Centers for Disease Control and Prevention (CDC) issued guidelines for opioid prescriptions, and the following year the VA and the US Department of Defense (DoD) updated the VA/DoD Clinical Practice Guidelines for Opioid Therapy for Chronic Pain (VA/DoD guidelines).^4,5 After the release of these guidelines, the use of opioid tapers expanded. However, due to public outcry of forced opioid tapering in 2019, the US Food and Drug Administration updated its opioid labeling requirements to provide clearer guidance on opioid tapers for tolerant patients.^6,7

As a result, HCPs began to develop various strategies to balance the safety and efficacy of opioid use in patients with chronic pain. The West Palm Beach VA Medical Center (WPBVAMC) in Florida has a Pain Clinic that includes 2 pain management clinical pharmacy specialists (CPSs) with specialized training in pain management, who are uniquely qualified to assess and evaluate medication therapy in complex pain patient cases. These CPSs were involved in the face-to-face management of patients requiring specialized pain care and participated in a pain pharmacy electronic consult (eConsult) service to document pain management consultative recommendations for patients appropriate for management at the primary care level. This formalized process increased specialty pain care access for veterans whose pain was managed by primary care providers (PCPs).

The pain pharmacy eConsult service was initiated at the WPBVAMC in June 2013 to assist PCPs in the management of outpatients with chronic pain. The eConsult service includes evaluation of a patient’s electronic health records (EHRs) by CPSs. The eConsult service also provided PCPs with the option to engage a pharmacist who could provide recommendations for opioid dosing conversion, opioid tapering, pain pharmacotherapy, or drug screen interpretation, without the necessity for an additional patient visit.

Subsequent to the release of the 2016 CDC (and later the 2017 VA/DoD) guidelines recommending reducing morphine equivalent daily dose (MEDD) levels, the WPBVAMC had a large increase in pain eConsult requests for opioid tapering and opioid pharmacotherapy. A 3.4-fold increase in requests occurred in March, April, and May vs the following 9 months, and a nearly 4-fold increase in requests for opioid tapers during the same period. However, the impact of the completed eConsults was unclear. Therefore, the primary objective of this study was to assess the effect of CPS services for opioid tapering and opioid pharmacotherapy by quantifying the number of recommendations accepted/implemented by PCPs. The secondary objectives included evaluating harms associated with the recommendations (eg, increase in visits to the emergency department [ED], hospitalizations, suicide attempts, or PCP visits) and provider satisfaction.

Methods

A retrospective chart review was completed to assess data of patients from the WPBVAMC and its associated community-based outpatient clinics (CBOCs). The project was approved by the WPBVAMC Scientific Advisory Committee as part of the facility’s performance improvement efforts.

Included patients had a pain pharmacy eConsult placed between April 1, 2016 and March 31, 2017. EHRs were reviewed and only eConsults for opioid pharmacotherapy recommendation or opioid tapers were evaluated. eConsults were excluded if the request was discontinued, completed by a HCP other than the pain CPS, or placed for an opioid dose conversion, nonopioid pharmacotherapy, or drug screen interpretation.

Data for analyses were entered into Microsoft Excel 2016 and were securely saved and accessible to relevant researchers. Patient protected health information used during patient care remained confidential.

Demographic data were collected, including age, gender, race, pertinent medical comorbidities (eg, diabetes mellitus, sleep apnea), and mental health comorbidities. Pain scores were collected at baseline and 6-months postconsult. Pain medications used by patients were noted at baseline and 6 months postconsult, including concomitant opioid and benzodiazepine use, MEDD, and other pain medication. The duration of time needed by pain CPS to complete each eConsult and total time from eConsult entered to HCP implementation of the initial recommendation was collected. The number of actionable recommendations (eg, changes in drug therapy, urine drug screens [UDSs], and referrals to other services also were recorded and reviewed 6 months postconsult to determine the number and percentage of recommendations implemented by the HCP. The EHR was examined to determine adverse events (AEs) (eg, any documentation of suicide attempt, calls to the Veterans Crisis Line, or death 6 month postconsult). Collected data also included new eConsults, the reason for opioid tapering either by HCP or patient, and assessment of economic harms (count of the number of visits to ED, hospitalizations, or unscheduled PCP visits with uncontrolled pain as chief reason within 6 months postconsult). Last, PCPs were sent a survey to assess their satisfaction with the pain eConsult service.

Results

Of 517 eConsults received from April 1, 2016 to March 31, 2017, 285 (55.1%) met inclusion criteria (Figure). Using a random number generator, 100 eConsults were further reviewed for outcomes of interest.

In this cohort, the mean age was 61 years, 87% were male, and 80% were White individuals. Most patients (83%) had ≥ 1 mental health comorbidity, and 53% had ≥ 2, with depressive symptoms, tobacco use, and/or posttraumatic stress disorder the most common diagnoses (Table 1). Eighty-seven percent of eConsults were for opioid tapers and the remaining 13% were for opioid pharmacotherapy.

The median pain score at time of consult was 6 on a 10-point scale, with no change at 6 months postconsult. However, 41% of patients overall had a median 3.3-point drop in pain score, 17% had no change in pain score, and 42% had a median 2.6-point increase in pain score.

Electronic Consults

Table 2 describes the reasons eConsults were requested. The most common reason was to taper the dose to be in compliance with the CDC 2016 guideline recommendation of MEDD < 90 mg, which was later increased to 100 mg by the VA/DoD guideline.

On average, eConsults were completed within a mean of 11.5 days of the PCP request, including nights and weekends. The CPS spent a mean 66.8 minutes to complete each eConsult. Once the eConsult was completed, PCPs took a mean of 9 days to initiate the primary recommendation. This 9-day average does not include 11 eConsults with no accepted recommendations and 11 eConsults for which the PCP implemented the primary recommendation before the CPS completed the consult, most likely due to a phone call or direct contact with the CPS at the time the eConsult was ordered.

A mean 3.5 actionable recommendations were made by the CPS and a mean 1.6 recommendations were implemented within 6 months by the PCP. At least 1 recommendation was accepted/implemented for 89% of patients, with a mean 55% recommendations that were accepted/implemented. Eleven percent of the eConsult final recommendations were not accepted by PCPs and clear documentation of the reasons were not provided.

In the 6 months postconsult, 11 patients (7 men and 4 women) experienced 32 AEs (Table 3). Eight patients had 15 ED visits, with 3 of the visits resulting in hospitalizations, 8 patients had 9 unscheduled PCP visits, 1 patient reported suicidal ideation and 2 patients made a total of 4 calls to the Veterans Crisis Line. There were also 2 deaths; however, both were due to end-stage disease (cirrhosis and amyotrophic lateral sclerosis) and not believed to be related to eConsult recommendations.

Eight patients had a history of substance use disorders (SUDs) and 8 had a history of a mood disorder or psychosis. One patient had both SUD and a mood/psychosis-related mental health disorder, including a reported suicidal attempt/ideation at an ED visit and a subsequent hospitalization. A similar number of AEs occurred in patients with decreases in MEDD of 0 to 24% compared with those that received more aggressive tapers of 75 to 100% (Table 4).

Primary Care Providers

Nine patients were reconsulted, with only 1 secondary to the PCP not implementing recommendations from the initial consult. No factors were found that correlated with likelihood of a patient being reconsulted.

Surveys on PCP satisfaction with the eConsult service were completed by 29 of the 55 PCPs. PCP feedback was generally positive with nearly 90% of PCPs planning to use the service in the future as well as recommending use to other providers.

Discussion

Most (89%) PCPs accepted at least 1 recommendation from the completed eConsult, and MEDDs decreased by 60%, likely reducing the patient’s risk of overdose or other AEs from opioids. There also was a slight reduction in patient’s mean pain scores; however, 41% had a decrease and 42% had an increase in pain scores. There was no clear relationship when pain scores were compared with MEDDs, likely giving credence to the idea that pain scores are largely subjective and an unreliable surrogate marker for assessing effectiveness of analgesic regimens.

Eleven patients experienced AEs, including 1 patient for whom the recommendations were not implemented by the PCP. Eight of the 11 had multiple AEs. One interesting finding was that 7 of the 11 patients with an AE tested positive for unexpected substances on routine UDS or were arrested for driving while intoxicated (DWI). However, only 3 of the 7 had an active SUD diagnosis. With 25% of the AEs coming from patients with a history of SUD, it is important that any history of SUD be documented in the EHR. Maintaining this documentation can be especially difficult if patients switch VA medical centers or receive services outside the VA. Thorough and accurate history and chart review should ideally be completed before prescribing opioids.

Guidelines

While the PCPs were following VA/DoD and CDC recommendations for opioid tapering to < 100 or 90 mg MEDD, respectively, there is weak evidence in these guidelines to support specific MEDD cutoffs. The CDC guidelines even state, “a single dosage threshold for safe opioid use could not be identified.”⁵ One of the largest issues when using MEDD as a cutoff is the lack of agreement on its calculation. In 2014, Nuckols and colleagues al conducted a study to compare the existing guidelines on the use of opioids for chronic pain. While 13 guidelines were considered eligible, most recommendations were supported only by observational data or expert recommendations, and there was no consensus on what constitutes a “morphine equivalent.”⁸ Currently there is no universally accepted opioid-conversion method, resulting in a substantial problem when calculating a MEDD.⁹ A survey of 8 online opioid dose conversion tools found a -55% to +242% variation.¹⁰ As Fudin and colleagues concluded in response to the large variations found in these various analyses, the studies “unequivocally disqualify the validity of embracing MEDD to assess risk in any meaningful statistical way.”¹¹ Pharmacogenetics, drug tolerance, drug-drug interactions, body surface area, and organ function are patient- specific factors that are not taken into consideration when relying solely on a MEDD calculation. Tapering to lowest functional dose rather than a specific number or cutoff may be a more effective way to treat patients, and providers should use the guidelines as recommendations and not a hardline mandate.

At 6 months, 6 patients were receiving no pain medications from the VA, and 24 of the patients were tapered from their opiate to discontinuation. It is unclear whether patients are no longer taking opioids or switched their care to non-VA providers to receive medications, including opioids, privately. This is difficult to verify, though a prescription drug monitoring program (PDMP) could be used to assess patient adherence. As many of the patients that were tapered due to identification of aberrant behaviors, lack of continuity of care across health care systems may result in future patient harm.

The results of this analysis highlight the importance of checking PDMP databases and routine UDSs when prescribing opioids—there can be serious safety concerns if patients are taking other prescribed or illicit medications. However, care must be taken; there were 2 instances of patients’ chronic opioid prescriptions discontinued by their VA provider after a review of the PDMP showed they had received non-VA opioids. In both cases, the quantity and doses received were small (counts of ≤ 12) and were received more than 6 months prior to the check of the PDMP. While this constitutes a breach of the Informed Consent for long-term opioid use, if there are no other concerning behaviors, it may be more prudent to review the informed consent with the patient and discuss why the behavior is a breach to ensure that patients and PCPs continue to work as a team to manage chronic pain.

Limitations

The study population was one limitation of this project. While data suggest that chronic pain affects women more than men, this study’s population was only 13% female. Thirty percent of the women in this study had an AE compared with only 8% of the men. Additional limitations included use of problem list for comorbidities, as lists may be inaccurate or outdated, and limiting the monitoring of AE to only 6 months. As some tapers were not initiated immediately and some taper schedules can last several months to years; therefor, outcomes may have been higher if patients were followed longer. Many of the patients with AEs had increased ED visits or unscheduled primary care visits as the tapers went on and their pain worsened, but the visits were outside the 6-month time frame for data collection. An additional weakness of this review included assessing a pain score, but not functional status, which may be a better predictor of the effectiveness of a patient’s pain management regimen. This assessment is needed in future studies for more reliable data. Finally, PCP survey results also should be viewed with caution. The current survey had only 29 respondents, and the 2014 survey had only 10 respondents and did not include CBOC providers.

Conclusion

A pain eConsult service managed by CPSs specializing in pain management can assist patients and PCPs with opioid therapy recommendations in a safe and timely manner, reducing risk of overdose secondary to high dose opioid therapy and with limited harm to patients.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

Total knee arthroplasty (TKA) is one of the most common surgical procedures in the United States. The volume of TKAs is projected to substantially increase over the next 30 years.¹ Adequate pain control after TKA is critically important to achieve early mobilization, shorten the length of hospital stay, and reduce postoperative complications. The evolution and inclusion of multimodal pain-management protocols have had a major impact on the clinical outcomes for TKA patients.^2,3

Pain-management protocols typically use several modalities to control pain throughout the perioperative period. Multimodal opioid and nonopioid oral medications are administered during the pre- and postoperative periods and often involve a combination of acetaminophen, gabapentinoids, and cyclooxygenase-2 inhibitors.⁴ Peripheral nerve blocks and central neuraxial blockades are widely used and have been shown to be effective in reducing postoperative pain as well as overall opioid consumption.^5,6 Finally, intraoperative periarticular injections have been shown to reduce postoperative pain and opioid consumption as well as improve patient satisfaction scores.^7-9 These strategies are routinely used in TKA with the goal of minimizing overall opioid consumption and adverse events, reducing perioperative complications, and improving patient satisfaction.

Periarticular injections during surgery are an integral part of the multimodal pain-management protocols, though no consensus has been reached on proper injection formulation or technique. Liposomal bupivacaine is a local anesthetic depot formulation approved by the US Food and Drug Administration for surgical patients. The reported results have been discrepant regarding the efficacy of using liposomal bupivacaine injection in patients with TKA. Several studies have reported no added benefit of liposomal bupivacaine in contrast to a mixture of local anesthetics.^10,11 Other studies have demonstrated superior pain relief.¹² Many factors may contribute to the discrepant data, such as injection techniques, infiltration volume, and the assessment tools used to measure efficacy and safety.¹³

The US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care to a large patient population. Many of the patients in that system have high-risk profiles, including medical comorbidities; exposure to chronic pain and opioid use; and psychological and central nervous system injuries, including posttraumatic stress disorder and traumatic brain injury. Hadlandsmyth and colleagues reported increased risk of prolonged opioid use in VA patients after TKA surgery.¹⁴ They found that 20% of the patients were still on long-term opioids more than 90 days after TKA.

The purpose of this study was to evaluate the efficacy of the implementation of a comprehensive enhanced recovery after surgery (ERAS) protocol at a regional VA medical center. We hypothesize that the addition of liposomal bupivacaine in a multidisciplinary ERAS protocol would reduce the length of hospital stay and opioid consumption without any deleterious effects on postoperative outcomes.

Methods

A postoperative recovery protocol was implemented in 2013 at VA North Texas Health Care System (VANTHCS) in Dallas, and many of the patients continued to have issues with satisfactory pain control, prolonged length of stay, and extended opioid consumption postoperatively. A multimodal pain-management protocol and multidisciplinary perioperative case-management protocol were implemented in 2016 to further improve the clinical outcomes of patients undergoing TKA surgery. The senior surgeon (JM) organized a multidisciplinary team of health care providers to identify and implement potential solutions. This task force met weekly and consisted of surgeons, anesthesiologists, certified registered nurse anesthetists, orthopedic physician assistants, a nurse coordinator, a physical therapist, and an occupational therapist, as well as operating room, postanesthesia care unit (PACU), and surgical ward nurses. In addition, the staff from the home health agencies and social services attended the weekly meetings.

We conducted a retrospective review of all patients who had undergone unilateral TKA from 2013 to 2018 at VANTHCS. This was a consecutive, unselected cohort. All patients were under the care of a single surgeon using identical implant systems and identical surgical techniques. This study was approved by the institutional review board at VANTHCS. Patients were divided into 2 distinct and consecutive cohorts. The standard of care (SOC) group included all patients from 2013 to 2016. The ERAS group included all patients after the institution of the standardized protocol until the end of the study period.

Data on patient demographics, the American Society of Anesthesiologists risk classification, and preoperative functional status were extracted. Anesthesia techniques included either general endotracheal anesthesia or subarachnoid block with monitored anesthesia care. The quantity of the opioids given during surgery, in the PACU, during the inpatient stay, as discharge prescriptions, and as refills of the narcotic prescriptions up to 3 months postsurgery were recorded. All opioids were converted into morphine equivalent dosages (MED) in order to be properly analyzed using the statistical methodologies described in the statistical section.¹⁵ The VHA is a closed health care delivery system; therefore, all of the prescriptions ordered by surgery providers were recorded in the electronic health record.

ERAS Protocol

The SOC cohort was predominantly managed with general endotracheal anesthesia. The ERAS group was predominantly managed with subarachnoid blocks (Table 1). For the ERAS protocol preoperatively, the patients were administered oral gabapentin 300 mg, acetaminophen 650 mg, and oxycodone 20 mg, and IV ondansetron 4 mg. Intraoperatively, minimal opioids were used. In the PACU, the patients received dilaudid 0.25 mg IV as needed every 15 minutes for up to 1 mg/h. The nursing staff was trained to use the visual analog pain scale scores to titrate the medication. During the inpatient stay, patients received 1 g IV acetaminophen every 6 hours for 3 doses. The patients thereafter received oral acetaminophen as needed. Other medications in the multimodal pain-management protocol included gabapentin 300 mg twice daily, meloxicam 15 mg daily, and oxycodone 10 mg every 4 hours as needed. Rescue medication for insufficient pain relief was dilaudid 0.25 mg IV every 15 minutes for visual analog pain scale > 8. On discharge, the patients received a prescription of 30 tablets of hydrocodone 10 mg.

Periarticular Injections

Intraoperatively, all patients in the SOC and ERAS groups received periarticular injections. The liposomal bupivacaine injection was added to the standard injection mixture for the ERAS group. For the SOC group, the total volume of 100 ml was divided into 10 separate 10 cc syringes, and for the ERAS group, the total volume of 140 ml was divided into 14 separate 10 cc syringes. The SOC group injections were performed with an 18-gauge needle and the periarticular soft tissues grossly infiltrated. The ERAS group injections were done with more attention to anatomical detail. Injection sites for the ERAS group included the posterior joint capsule, the medial compartment, the lateral compartment, the tibial fat pad, the quadriceps and the patellar tendon, the femoral and tibial periosteum circumferentially, and the anterior joint capsule. Each needle-stick in the ERAS group delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee.

Outcome Variable

The primary outcome measure was total oral MED intraoperatively, in the PACU, during the hospital inpatient stay, in the hospital discharge prescription, and during the 3-month period after hospital discharge. Incidence of nausea and vomiting during the inpatient stay and any narcotic use at 6 months postsurgery were secondary binary outcomes.

Statistical Analysis

Demographic data and the clinical characteristics for the entire group were described using the sample mean and SD for continuous variables and the frequency and percentage for categorical variables. Differences between the 2 cohorts were analyzed using a 2-independent-sample t test and Fisher exact test.

The estimation of the total oral MED throughout all phases of care was done using a separate Poisson model due to the data being not normally distributed. A log-linear regression model was used to evaluate the main effect of ERAS vs the SOC cohort on the total oral MED used. Finally, a separate multiple logistic regression model was used to estimate the odds of postoperative nausea and vomiting and narcotic use at 6 months postsurgery between the cohorts. The adjusted odds ratio (OR) was estimated from the logistic model. Age, sex, body mass index, preoperative functional independence score, narcotic use within 3 months prior to surgery, anesthesia type used (subarachnoid block with monitored anesthesia care vs general endotracheal anesthesia), and postoperative complications (yes/no) were included as covariates in each model. The length of hospital stay and the above-mentioned factors were also included as covariates in the model estimating the total oral MED during the hospital stay, on hospital discharge, during the 3-month period after hospital discharge, and at 6 months following hospital discharge.

Results

Two hundred forty-nine patients had 296 elective unilateral TKAs in this study from 2013 through 2018. Thirty-one patients had both unilateral TKAs under the SOC protocol; 5 patients had both unilateral TKAs under the ERAS protocol. Eleven of the patients who eventually had both knees replaced had 1 operation under each protocol The SOC group included 196 TKAs and the ERAS group included 100 TKAs. Of the 196 SOC patients, 94% were male. The mean age was 68.2 years (range, 48-86). The length of hospital stay ranged from 36.6 to 664.3 hours. Of the 100 ERAS patients, 96% were male (Table 2). The mean age was 66.7 years (range, 48-85). The length of hospital stay ranged from 12.5 to 45 hours.

Perioperative Opioid Use

Of the SOC patients, 99.0% received narcotics intraoperatively (range, 0-198 mg MED), and 74.5% received narcotics during PACU recovery (range, 0-141 mg MED). The total oral MED during the hospital stay for the SOC patients ranged from 10 to 2,946 mg. Of the ERAS patients, 86% received no narcotics during surgery (range, 0-110 mg MED), and 98% received no narcotics during PACU recovery (range, 0-65 mg MED). The total oral MED during the hospital stay for the ERAS patients ranged from 10 to 240 mg.

The MED used was significantly lower for the ERAS patients than it was for the SOC patients during surgery (10.5 mg vs 57.4 mg, P = .0001, FDR = .0002) and in the PACU (1.3 mg vs 13.6 mg, P = .0002, FDR = .0004), during the inpatient stay (66.7 mg vs 169.5 mg, P = .0001, FDR = .0002), and on hospital discharge (419.3 mg vs 776.7 mg, P = .0001, FDR = .0002). However, there was no significant difference in the total MED prescriptions filled between patients on the ERAS protocol vs those who received SOC during the 3-month period after hospital discharge (858.3 mg vs 1126.1 mg, P = .29, FDR = .29)(Table 3).

Discussion

Orthopedic surgery has been associated with long-term opioid use and misuse. Orthopedic surgeons are frequently among the highest prescribers of narcotics. According to Volkow and colleagues, orthopedic surgeons were the fourth largest prescribers of opioids in 2009, behind primary care physicians, internists, and dentists.¹⁷ The opioid crisis in the United States is well recognized. In 2017, > 70,000 deaths occurred due to drug overdoses, with 68% involving a prescription or illicit opioid. The Centers for Disease Control and Prevention has estimated a total economic burden of $78.5 billion per year as a direct result of misused prescribed opioids.¹⁸ This includes the cost of health care, lost productivity, addiction treatment, and the impact on the criminal justice system.

The current opioid crisis places further emphasis on opioid-reducing or sparing techniques in patients undergoing TKA. The use of liposomal bupivacaine for intraoperative periarticular injection is debated in the literature regarding its efficacy and whether it should be included in multimodal protocols. Researchers have argued that liposomal bupivacaine is not superior to regular bupivacaine and because of its increased cost is not justified.^19,20 A meta-analysis from Zhao and colleagues showed no difference in pain control and functional recovery when comparing liposomal bupivacaine and control.²¹ In a randomized clinical trial, Schroer and colleagues matched liposomal bupivacaine against regular bupivacaine and found no difference in pain scores and similar narcotic use during hospitalization.²²

Studies evaluating liposomal bupivacaine have demonstrated postoperative benefits in pain relief and potential opioid consumption.²³ In a multicenter randomized controlled trial, Barrington and colleagues noted improved pain control at 6 and 12 hours after surgery with liposomal bupivacaine as a periarticular injection vs ropivacaine, though results were similar when compared with intrathecal morphine.²⁴ Snyder and colleagues reported higher patient satisfaction in pain control and overall experience as well as decreased MED consumption in the PACU and on postoperative days 0 to 2 when using liposomal bupivacaine vs a multidrug cocktail for periarticular injection.²⁵

The PILLAR trial, an industry-sponsored study, was designed to compare the effects of local infiltration anesthesia with and without liposomal bupivacaine with emphasis on a meticulous standardized infiltration technique. In our study, we used a similar technique with an expanded volume of injection solution to 140 ml that was delivered throughout the knee in a series of 14 syringes. Each needle-stick delivered 1 to 1.5 ml through a 22-gauge needle to each compartment of the knee. Infiltration technique has varied among the literature focused on periarticular injections.

In our experience, a standard infiltration technique is critical to the effective delivery of liposomal bupivacaine throughout all compartments of the knee and to obtaining reproducible pain control. The importance of injection technique cannot be overemphasized, and variations can be seen in studies published to date.²⁶ Well-designed trials are needed to address this key component.

There have been limited data focused on the veteran population regarding postoperative pain-management strategies and recovery pathways either with or without liposomal bupivacaine. In a retrospective review, Sakamoto and colleagues found VA patients undergoing TKA had reduced opioid use in the first 24 hours after primary TKA with the use of intraoperative liposomal bupivacaine.²⁷ The VA population has been shown to be at high risk for opioid misuse. The prevalence of comorbidities such as traumatic brain injury, posttraumatic stress disorder, and depression in the VA population also places them at risk for polypharmacy of central nervous system–acting medications.²⁸ This emphasizes the importance of multimodal strategies, which can limit or eliminate narcotics in the perioperative period. The implementation of our ERAS protocol reduced opioid use during intraoperative, PACU, and inpatient hospital stay.

While the financial implications of our recovery protocol were not a primary focus of this study, there are many notable benefits on the overall inpatient cost to the VHA. According to the Health Economics Resource Center, the average daily cost of stay while under VA care for an inpatient surgical bed increased from $4,831 in 2013 to $6,220 in 2018.²⁹ Our reduction in length of stay between our cohorts is 44.5 hours, which translates to a substantial financial savings per patient after protocol implementation. A more detailed look at the financial aspect of our protocol would need to be performed to evaluate the financial impact of other aspects of our protocol, such as the elimination of patient-controlled anesthesia and the reduction in total narcotics prescribed in the postoperative global period.

Limitations

The limitations of this study include its retrospective study design. With the VHA patient population, it may be subject to selection bias, as the population is mostly older and predominantly male compared with that of the general population. This could potentially influence the efficacy of our protocol on a population of patients with more women. In a recent study by Perruccio and colleagues, sex was found to moderate the effects of comorbidities, low back pain, and depressive symptoms on postoperative pain in patients undergoing TKA.³⁰

With regard to outpatient narcotic prescriptions, although we cannot fully know whether these filled prescriptions were used for pain control, it is a reasonable assumption that patients who are dealing with continued postoperative or chronic pain issues will fill these prescriptions or seek refills. It is important to note that the data on prescriptions and refills in the 3-month postoperative period include all narcotic prescriptions filled by any VHA prescriber and are not specifically limited to our orthopedic team. For outpatient narcotic use, we were not able to access accurate pill counts for any discharge prescriptions or subsequent refills that were given throughout the VA system. We were able to report on total prescriptions filled in the first 3 months following TKA.

We calculated total oral MEDs to better understand the amount of narcotics being distributed throughout our population of patients. We believe this provides important information about the overall narcotic burden in the veteran population. There was no significant difference between the SOC and ERAS groups regarding oral MED prescribed in the 3-month postoperative period; however, at the 6-month follow-up visit, only 16% of patients in the ERAS group were taking any type of narcotic vs 37.2% in the SOC group (P = .0002).

Conclusions

A multidisciplinary ERAS protocol implemented at VANTHCS was effective in reducing length of stay and opioid burden throughout all phases of surgical care in our patients undergoing primary TKA. Patient and nursing education seem to be critical components to the implementation of a successful multimodal pain protocol. Reducing the narcotic burden has valuable financial and medical benefits in this at-risk population.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

NSAIDs don’t boost the risk of more severe disease or death in hospitalized patients with COVID-19, a new study finds.

Denise Fulton/MDedge News

“To our knowledge, our prospective study includes the largest number of patients admitted to hospital with COVID-19 to date, and adds to the literature on the safety of NSAIDs and in-hospital outcomes. NSAIDs do not appear to increase the risk of worse in-hospital outcomes ...” the study authors wrote. “NSAIDs are an important analgesic modality and have a vital opioid-sparing role in pain management. Patients and clinicians should be reassured by these findings that NSAIDs are safe in the context of the pandemic.”

The report was published online May 7 in The Lancet Rheumatology and led by clinical research fellow Thomas M. Drake, MBChB, of the University of Edinburgh’s Usher Institute.

For more than a year, researchers worldwide have debated about whether NSAIDs spell trouble for people at risk of COVID-19. In March 2020, French health officials announced that use of the painkillers such as NSAIDs may increase the severity of the disease, and they recommended that patients take acetaminophen instead. The National Health Service in the United Kingdom made a similar recommendation. But other agencies didn’t believe there was enough evidence to support ditching NSAIDs, and recent research studies published in Annals of the Rheumatic Diseases and PLoS Medicine suggested they may be right.

For the new study, researchers identified 72,179 patients who were treated for COVID-19 in British hospitals during January-August 2020. About 56% were men, 74% were White, and 6% took NSAIDs on a regular basis before they entered the hospital. The average age was 70.

The researchers examined whether the patients in either group were more or less likely to die in the hospital, be admitted into a critical care unit, need oxygen treatment, need a ventilator, or suffer kidney injury.

In terms of outcomes, there weren’t any major gaps between the groups overall. The differences in most comparisons were statistically insignificant. For example, 31% of those who didn’t take NSAIDs died vs. 30% of those who did (P = .227). In both groups, 14% required critical care admission (P = .476).

The researchers then focused on two matched groups of 4,205 patients: One group used NSAIDs regularly, and the other group didn’t. The difference in risk of death in those who took NSAIDs vs. those who didn’t was statistically insignificant (odds ratio, 0.95; 95% confidence interval, 0.84-1.07; P = .35). Other comparisons were also statistically insignificant.

The findings offer insight into whether the use of NSAIDs might actually be helpful for patients who develop COVID-19. Scientists believe that COVID-19 is linked to inflammation in the body, and NSAIDs, of course, reduce inflammation. But the researchers didn’t turn up any sign of a benefit.

The new study has some weaknesses: It doesn’t say anything about whether NSAIDs have an impact on whether people get COVID-19 in the first place. Researchers don’t know if high use of NSAIDs may affect the severity of the disease. And it doesn’t examine the potential effect of acetaminophen, although other research suggests the drug also may not cause harm in patients with COVID-19.

Still, the researchers say the study is the largest of its kind to look at the use of NSAIDs by patients who are admitted to the hospital with COVID-19. “Considering all the evidence, if there was an extreme effect of NSAIDs on COVID-19 outcomes or severity, this would have been observed in one or more of the studies that have been done, including the present study,” they wrote.

In a commentary that accompanied the study, three physicians from hospitals in Denmark, led by Kristian Kragholm, MD, of Aalborg University Hospital, praised the research and wrote that it adds to “a growing body of evidence” that NSAIDs don’t make things worse for patients with COVID-19.

The study was funded by the U.K. National Institute for Health Research and the U.K. Medical Research Council. The study and commentary authors reported no relevant disclosures.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Nearly one out of five American adults with hypertension is on a prescription drug known to raise blood pressure, based on analysis of more than 27,000 people included in recent reports from the recurring National Health and Nutrition Examination Survey (NHANES).

Nearly half of these American adults had hypertension, and in this subgroup, 18.5% reported using a prescription drug known to increase blood pressure. The most widely used class of agents with this effect was antidepressants, used by 8.7%; followed by nonsteroidal anti-inflammatory drugs (NSAIDs), used by 6.5%; steroids, 1.9%; estrogens, 1.7%; and several other agents each used by fewer than 1% of the study cohort, John Vitarello, MD, said during a press briefing on reports from the upcoming annual scientific sessions of the American College of Cardiology.

He and his associates estimated that this use of prescription drugs known to raise blood pressure could be what stands in the way of some 560,000-2.2 million Americans from having their hypertension under control, depending on the exact blood pressure impact that various pressure-increasing drugs have and presuming that half of those on blood pressure increasing agents could stop them and switch to alternative agents, said Dr. Vitarello, a researcher at Beth Israel Deaconess Medical Center in Boston.

He also highlighted that the study assessed only prescription drugs and did not examine OTC drug use, which may be especially relevant for the many people who regularly take NSAIDs.

“Clinicians should review the prescription and OTC drug use of patients with hypertension and consider stopping drugs that increase blood pressure or switching the patient to alternatives” that are blood pressure neutral, Dr. Vitarello said during the briefing. He cautioned that maintaining hypertensive patients on agents that raise their blood pressure can result in “prescribing cascades” where taking drugs that boost blood pressure results in need for intensified antihypertensive treatment.
 

An opportunity for NSAID alternatives

“This study hopefully raises awareness that there is a very high use of medications that increase blood pressure, and use of OTC agents could increase the rate even higher” said Eugene Yang, MD, a cardiologist and codirector of the Cardiovascular Wellness and Prevention Program of the University of Washington, Seattle. Substituting for certain antidepressant agents may often not be realistic, but an opportunity exists for reducing NSAID use, a class also linked with an increased risk for bleeding and other adverse effects, Dr. Yang said during the briefing. Minimizing use of NSAIDs including ibuprofen and naproxen use “is something to think about,” he suggested.

“The effect of NSAIDs on blood pressure is not well studied and can vary from person to person” noted Dr. Vitarello, who added that higher NSAID dosages and more prolonged use likely increase the risk for an adverse effect on blood pressure. One reasonable option is to encourage patients to use an alternative class of pain reliever such as acetaminophen.

It remains “a challenge” to discern differences in adverse blood pressure effects, and in all adverse cardiovascular effects among different NSAIDs, said Dr. Yang. Results from “some studies show that certain NSAIDs may be safer, but other studies did not. We need to be very careful using NSAIDs because, on average, they increase blood pressure by about 3 mm Hg. We need to be mindful to try to prescribe alternative agents, like acetaminophen.”
 

A decade of data from NHANES

The analysis run by Dr. Vitarello and associates used data from 27,599 American adults included in the NHANES during 2009-2018, and focused on the 44% who either had an average blood pressure measurement of at least 130/80 mm Hg or reported having ever been told by a clinician that they had hypertension. The NHANES assessments included the prescription medications taken by each participant. The prevalence of using at least one prescription drug known to raise blood pressure was 24% among women and 14% among men, and 4% of those with hypertension were on two or more pressure-increasing agents.

The researchers based their identification of pressure-increasing prescription drugs on the list included in the 2017 guideline for managing high blood pressure from the American College of Cardiology and American Heart Association. This list specifies that the antidepressants that raise blood pressure are the monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, and tricyclic antidepressants.

Dr. Vitarello and Dr. Yang had no disclosures.

[email protected]

Nearly one out of five American adults with hypertension is on a prescription drug known to raise blood pressure, based on analysis of more than 27,000 people included in recent reports from the recurring National Health and Nutrition Examination Survey (NHANES).

Nearly half of these American adults had hypertension, and in this subgroup, 18.5% reported using a prescription drug known to increase blood pressure. The most widely used class of agents with this effect was antidepressants, used by 8.7%; followed by nonsteroidal anti-inflammatory drugs (NSAIDs), used by 6.5%; steroids, 1.9%; estrogens, 1.7%; and several other agents each used by fewer than 1% of the study cohort, John Vitarello, MD, said during a press briefing on reports from the upcoming annual scientific sessions of the American College of Cardiology.

He and his associates estimated that this use of prescription drugs known to raise blood pressure could be what stands in the way of some 560,000-2.2 million Americans from having their hypertension under control, depending on the exact blood pressure impact that various pressure-increasing drugs have and presuming that half of those on blood pressure increasing agents could stop them and switch to alternative agents, said Dr. Vitarello, a researcher at Beth Israel Deaconess Medical Center in Boston.

He also highlighted that the study assessed only prescription drugs and did not examine OTC drug use, which may be especially relevant for the many people who regularly take NSAIDs.

“Clinicians should review the prescription and OTC drug use of patients with hypertension and consider stopping drugs that increase blood pressure or switching the patient to alternatives” that are blood pressure neutral, Dr. Vitarello said during the briefing. He cautioned that maintaining hypertensive patients on agents that raise their blood pressure can result in “prescribing cascades” where taking drugs that boost blood pressure results in need for intensified antihypertensive treatment.
 

An opportunity for NSAID alternatives

“This study hopefully raises awareness that there is a very high use of medications that increase blood pressure, and use of OTC agents could increase the rate even higher” said Eugene Yang, MD, a cardiologist and codirector of the Cardiovascular Wellness and Prevention Program of the University of Washington, Seattle. Substituting for certain antidepressant agents may often not be realistic, but an opportunity exists for reducing NSAID use, a class also linked with an increased risk for bleeding and other adverse effects, Dr. Yang said during the briefing. Minimizing use of NSAIDs including ibuprofen and naproxen use “is something to think about,” he suggested.

“The effect of NSAIDs on blood pressure is not well studied and can vary from person to person” noted Dr. Vitarello, who added that higher NSAID dosages and more prolonged use likely increase the risk for an adverse effect on blood pressure. One reasonable option is to encourage patients to use an alternative class of pain reliever such as acetaminophen.

It remains “a challenge” to discern differences in adverse blood pressure effects, and in all adverse cardiovascular effects among different NSAIDs, said Dr. Yang. Results from “some studies show that certain NSAIDs may be safer, but other studies did not. We need to be very careful using NSAIDs because, on average, they increase blood pressure by about 3 mm Hg. We need to be mindful to try to prescribe alternative agents, like acetaminophen.”
 

A decade of data from NHANES

The analysis run by Dr. Vitarello and associates used data from 27,599 American adults included in the NHANES during 2009-2018, and focused on the 44% who either had an average blood pressure measurement of at least 130/80 mm Hg or reported having ever been told by a clinician that they had hypertension. The NHANES assessments included the prescription medications taken by each participant. The prevalence of using at least one prescription drug known to raise blood pressure was 24% among women and 14% among men, and 4% of those with hypertension were on two or more pressure-increasing agents.

The researchers based their identification of pressure-increasing prescription drugs on the list included in the 2017 guideline for managing high blood pressure from the American College of Cardiology and American Heart Association. This list specifies that the antidepressants that raise blood pressure are the monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, and tricyclic antidepressants.

Dr. Vitarello and Dr. Yang had no disclosures.

[email protected]

Nearly one out of five American adults with hypertension is on a prescription drug known to raise blood pressure, based on analysis of more than 27,000 people included in recent reports from the recurring National Health and Nutrition Examination Survey (NHANES).

Nearly half of these American adults had hypertension, and in this subgroup, 18.5% reported using a prescription drug known to increase blood pressure. The most widely used class of agents with this effect was antidepressants, used by 8.7%; followed by nonsteroidal anti-inflammatory drugs (NSAIDs), used by 6.5%; steroids, 1.9%; estrogens, 1.7%; and several other agents each used by fewer than 1% of the study cohort, John Vitarello, MD, said during a press briefing on reports from the upcoming annual scientific sessions of the American College of Cardiology.

He and his associates estimated that this use of prescription drugs known to raise blood pressure could be what stands in the way of some 560,000-2.2 million Americans from having their hypertension under control, depending on the exact blood pressure impact that various pressure-increasing drugs have and presuming that half of those on blood pressure increasing agents could stop them and switch to alternative agents, said Dr. Vitarello, a researcher at Beth Israel Deaconess Medical Center in Boston.

He also highlighted that the study assessed only prescription drugs and did not examine OTC drug use, which may be especially relevant for the many people who regularly take NSAIDs.

“Clinicians should review the prescription and OTC drug use of patients with hypertension and consider stopping drugs that increase blood pressure or switching the patient to alternatives” that are blood pressure neutral, Dr. Vitarello said during the briefing. He cautioned that maintaining hypertensive patients on agents that raise their blood pressure can result in “prescribing cascades” where taking drugs that boost blood pressure results in need for intensified antihypertensive treatment.
 

An opportunity for NSAID alternatives

“This study hopefully raises awareness that there is a very high use of medications that increase blood pressure, and use of OTC agents could increase the rate even higher” said Eugene Yang, MD, a cardiologist and codirector of the Cardiovascular Wellness and Prevention Program of the University of Washington, Seattle. Substituting for certain antidepressant agents may often not be realistic, but an opportunity exists for reducing NSAID use, a class also linked with an increased risk for bleeding and other adverse effects, Dr. Yang said during the briefing. Minimizing use of NSAIDs including ibuprofen and naproxen use “is something to think about,” he suggested.

“The effect of NSAIDs on blood pressure is not well studied and can vary from person to person” noted Dr. Vitarello, who added that higher NSAID dosages and more prolonged use likely increase the risk for an adverse effect on blood pressure. One reasonable option is to encourage patients to use an alternative class of pain reliever such as acetaminophen.

It remains “a challenge” to discern differences in adverse blood pressure effects, and in all adverse cardiovascular effects among different NSAIDs, said Dr. Yang. Results from “some studies show that certain NSAIDs may be safer, but other studies did not. We need to be very careful using NSAIDs because, on average, they increase blood pressure by about 3 mm Hg. We need to be mindful to try to prescribe alternative agents, like acetaminophen.”
 

A decade of data from NHANES

The analysis run by Dr. Vitarello and associates used data from 27,599 American adults included in the NHANES during 2009-2018, and focused on the 44% who either had an average blood pressure measurement of at least 130/80 mm Hg or reported having ever been told by a clinician that they had hypertension. The NHANES assessments included the prescription medications taken by each participant. The prevalence of using at least one prescription drug known to raise blood pressure was 24% among women and 14% among men, and 4% of those with hypertension were on two or more pressure-increasing agents.

The researchers based their identification of pressure-increasing prescription drugs on the list included in the 2017 guideline for managing high blood pressure from the American College of Cardiology and American Heart Association. This list specifies that the antidepressants that raise blood pressure are the monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, and tricyclic antidepressants.

Dr. Vitarello and Dr. Yang had no disclosures.

[email protected]

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.

The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.

Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
 

Conflicting results

Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.

All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.

Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.

The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.

“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.

The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.

[email protected]

Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.

The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.

Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
 

Conflicting results

Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.

All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.

Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.

The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.

“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.

The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.

[email protected]

Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.

The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.

Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
 

Conflicting results

Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.

All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.

Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.

The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.

“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.

The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.

[email protected]

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Although the healing properties of cannabis have been touted for millennia, research into its potential neuropsychiatric applications truly began to take off in the 1990s following the discovery of the cannabinoid system in the brain. This led to speculation that cannabis could play a therapeutic role in regulating dopamine, serotonin, and other neurotransmitters and offer a new means of treating various ailments.

LPETTET/Getty Images

At the same time, efforts to liberalize marijuana laws have successfully played out in several nations, including the United States, where, as of April 29, 36 states provide some access to cannabis. These dual tracks – medical and political – have made cannabis an increasingly accepted part of the cultural fabric.

Yet with this development has come a new quandary for clinicians. Medical cannabis has been made widely available to patients and has largely outpaced the clinical evidence, leaving it unclear how and for which indications it should be used.
 

The many forms of medical cannabis

Cannabis is a genus of plants that includes marijuana (Cannabis sativa) and hemp. These plants contain over 100 compounds, including terpenes, flavonoids, and – most importantly for medicinal applications – cannabinoids.

The most abundant cannabinoid in marijuana is the psychotropic delta-9-tetrahydrocannabinol (THC), which imparts the “high” sensation. The next most abundant cannabinoid is cannabidiol (CBD), which is the nonpsychotropic. THC and CBD are the most extensively studied cannabinoids, together and in isolation. Evidence suggests that other cannabinoids and terpenoids may also hold medical promise and that cannabis’ various compounds can work synergistically to produce a so-called entourage effect.

Patients walking into a typical medical cannabis dispensary will be faced with several plant-derived and synthetic options, which can differ considerably in terms of the ratios and amounts of THC and CBD they contain, as well in how they are consumed (i.e., via smoke, vapor, ingestion, topical administration, or oromucosal spray), all of which can alter their effects. Further complicating matters is the varying level of oversight each state and country has in how and whether they test for and accurately label products’ potency, cannabinoid content, and possible impurities.

Medically authorized, prescription cannabis products go through an official regulatory review process, and indications/contraindications have been established for them. To date, the Food and Drug Administration has approved one cannabis-derived drug product – Epidiolex (purified CBD) – for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged 2 years and older. The FDA has also approved three synthetic cannabis-related drug products – Marinol, Syndros (or dronabinol, created from synthetic THC), and Cesamet (or nabilone, a synthetic cannabinoid similar to THC) – all of which are indicated for treatment-related nausea and anorexia associated with weight loss in AIDS patients.

Surveys of medical cannabis consumers indicate that most people cannot distinguish between THC and CBD, so the first role that physicians find themselves in when recommending this treatment may be in helping patients navigate the volume of options.
 

Promising treatment for pain

Chronic pain is the leading reason patients seek out medical cannabis. It is also the indication that most researchers agree has the strongest evidence to support its use.

“In my mind, the most promising immediate use for medical cannabis is with THC for pain,” Diana M. Martinez, MD, a professor of psychiatry at Columbia University, New York, who specializes in addiction research, said in a recent MDedge podcast. “THC could be added to the armamentarium of pain medications that we use today.”

In a 2015 systematic literature review, researchers assessed 28 randomized, controlled trials (RCTs) of the use of cannabinoids for chronic pain. They reported that a variety of formulations resulted in at least a 30% reduction in the odds of pain, compared with placebo. A meta-analysis of five RCTs involving patients with neuropathic pain found a 30% reduction in pain over placebo with inhaled, vaporized cannabis. Varying results have been reported in additional studies for this indication. The National Academies of Sciences, Engineering, and Medicine concluded that there was a substantial body of evidence that cannabis is an effective treatment for chronic pain in adults.

The ongoing opioid epidemic has lent these results additional relevance. Data indicate that patients with chronic pain who undergo treatment with medical cannabis can reduce their intake of opioids by more than 60%.

Seeing this firsthand has caused Mark Steven Wallace, MD, a pain management specialist and chair of the division of pain medicine at the University of California San Diego Health, to reconsider offering cannabis to his patients.

“I think it’s probably more efficacious, just from my personal experience, and it’s a much lower risk of abuse and dependence than the opioids,” he said.

Dr. Wallace advised that clinicians who treat pain consider the ratios of cannabinoids.

“This is anecdotal, but we do find that with the combination of the two, CBD reduces the psychoactive effects of the THC. The ratios we use during the daytime range around 20 mg of CBD to 1 mg of THC,” he said.

In a recent secondary analysis of an RCT involving patients with painful diabetic peripheral neuropathy, Dr. Wallace and colleagues showed that THC’s effects appear to reverse themselves at a certain level.

“As the THC level goes up, the pain reduces until you reach about 16 ng/mL; then it starts going in the opposite direction, and pain will start to increase,” he said. “Even recreational cannabis users have reported that they avoid high doses because it’s very aversive. Using cannabis is all about, start low and go slow.”
 

A mixed bag for neurologic indications

There are relatively limited data on the use of medical cannabis for other neurologic conditions, and results have varied. For uses other than pain management, the evidence that does exist is strongest regarding epilepsy, said Daniel Freedman, DO, assistant professor of neurology at the University of Texas at Austin. He noted “multiple high-quality RCTs showing that pharmaceutical-grade CBD can reduce seizures associated with two particular epilepsy syndromes: Dravet Syndrome and Lennox Gastaut.”

These findings led to the FDA’s 2018 approval of Epidiolex for these syndromes. In earlier years, interest in CBD for pediatric seizures was largely driven by anecdotal parental reports of its benefits. NASEM’s 2017 overview on medical cannabis found evidence from subsequent RCTs in this indication to be insufficient. Clinicians who prescribe CBD for this indication must be vigilant because it can interact with several commonly used antiepileptic drugs.

Cannabinoid treatments have also shown success in alleviating muscle spasticity resulting from multiple sclerosis, most prominently in the form of nabiximols (Sativex), a standardized oralmucosal spray containing approximately equal quantities of THC and CBD. Nabiximols is approved in Europe but not in the United States. Moderate evidence supports the efficacy of these and other treatments over placebo in reducing muscle spasticity. Patient ratings of its effects tend to be higher than clinician assessment.

Parkinson’s disease has not yet been approved as an indication for treatment with cannabis or cannabinoids, yet a growing body of preclinical data suggests these could influence the dopaminergic system, said Carsten Buhmann, MD, from the department of neurology at the University Medical Center Hamburg-Eppendorf (Germany).

“In general, cannabinoids modulate basal-ganglia function on two levels which are especially relevant in Parkinson’s disease, i.e., the glutamatergic/dopaminergic synaptic neurotransmission and the corticostriatal plasticity,” he said. “Furthermore, activation of the endocannabinoid system might induce neuroprotective effects related to direct receptor-independent mechanisms, activation of anti-inflammatory cascades in glial cells via the cannabinoid receptor type 2, and antiglutamatergic antiexcitotoxic properties.”

Dr. Buhmann said that currently, clinical evidence is scarce, consisting of only four double-blind, placebo-controlled RCTs involving 49 patients. Various cannabinoids and methods of administering treatment were employed. Improvement was only observed in one of these RCTs, which found that the cannabinoid receptor agonist nabilone significantly reduced levodopa-induced dyskinesia for patients with Parkinson’s disease. Subjective data support a beneficial effect. In a nationwide survey of 1,348 respondents conducted by Dr. Buhmann and colleagues, the majority of medical cannabis users reported that it improved their symptoms (54% with oral CBD and 68% with inhaled THC-containing cannabis).

NASEM concluded that there was insufficient evidence to support the efficacy of medical cannabis for other neurologic conditions, including Tourette syndrome, amyotrophic lateral sclerosis, Huntington disease, dystonia, or dementia. A 2020 position statement from the American Academy of Neurology cited the lack of sufficient peer-reviewed research as the reason it could not currently support the use of cannabis for neurologic disorders.

Yet, according to Dr. Freedman, who served as a coauthor of the AAN position statement, this hasn’t stymied research interest in the topic. He’s seen a substantial uptick in studies of CBD over the past 2 years. “The body of evidence grows, but I still see many claims being made without evidence. And no one seems to care about all the negative trials.”
 

Cannabis as a treatment for, and cause of, psychiatric disorders

Mental health problems – such as anxiety, depression, and PTSD – are among the most common reasons patients seek out medical cannabis. There is an understandable interest in using cannabis and cannabinoids to treat psychiatric disorders. Preclinical studies suggest that the endocannabinoid system plays a prominent role in modulating feelings of anxiety, mood, and fear. As with opioids and chronic pain management, there is hope that medical cannabis may provide a means of reducing prescription anxiolytics and their associated risks.

The authors of the first systematic review (BMC Psychiatry. 2020 Jan 16;20[1]:24) of the use of medical cannabis for major psychiatric disorders noted that the current evidence was “encouraging, albeit embryonic.”

Meta-analyses have indicated a small but positive association between cannabis use and anxiety, although this may reflect the fact that patients with anxiety sought out this treatment. Given the risks for substance use disorders among patients with anxiety, CBD may present a more viable option. Positive results have been shown as treatment for generalized social anxiety disorder.

Limited but encouraging results have also been reported regarding the alleviation of PTSD symptoms with both cannabis and CBD, although the body of high-quality evidence hasn’t notably progressed since 2017, when NASEM declared that the evidence was insufficient. Supportive evidence is similarly lacking regarding the treatment of depression. Longitudinal studies suggest that cannabis use, particularly heavy use, may increase the risk of developing this disorder. Because THC is psychoactive, it is advised that it be avoided by patients at risk for psychotic disorders. However, CBD has yielded limited benefits for patients with treatment-resistant schizophrenia and for young people at risk for psychosis.

The use of medical cannabis for psychiatric conditions requires a complex balancing act, inasmuch as these treatments may exacerbate the very problems they are intended to alleviate.

Marta Di Forti, MD, PhD, professor of psychiatric research at Kings College London, has been at the forefront of determining the mental health risks of continued cannabis use. In 2019, Dr. Di Forti developed the first and only Cannabis Clinic for Patients With Psychosis in London where she and her colleagues have continued to elucidate this connection.

Dr. Di Forti and colleagues have linked daily cannabis use to an increase in the risk of experiencing psychotic disorder, compared with never using it. That risk was further increased among users of high-potency cannabis (≥10% THC). The latter finding has troubling implications, because concentrations of THC have steadily risen since 1970. By contrast, CBD concentrations have remained generally stable. High-potency cannabis products are common in both recreational and medicinal settings.

“For somebody prescribing medicinal cannabis that has a ≥10% concentration of THC, I’d be particularly wary of the risk of psychosis,” said Dr. Di Forti. “If you’re expecting people to use a high content of THC daily to medicate pain or a chronic condition, you even more so need to be aware that this is a potential side effect.”

Dr. Di Forti noted that her findings come from a cohort of recreational users, most of whom were aged 18-35 years.

“There have actually not been studies developed from collecting data in this area from groups specifically using cannabis for medicinal rather than recreational purposes,” she said.

She added that she personally has no concerns about the use of medical cannabis but wants clinicians to be aware of the risk for psychosis, to structure their patient conversations to identify risk factors or family histories of psychosis, and to become knowledgeable in detecting the often subtle signs of its initial onset.

When cannabis-associated psychosis occurs, Dr. Di Forti said it is primarily treated with conventional means, such as antipsychotics and therapeutic interventions and by refraining from using cannabis. Achieving the latter goal can be a challenge for patients who are daily users of high-potency cannabis. Currently, there are no treatment options such as those offered to patients withdrawing from the use of alcohol or opioids. Dr. Di Forti and colleagues are currently researching a solution to that problem through the use of another medical cannabis, the oromucosal spray Sativex, which has been approved in the European Union.
 

The regulatory obstacles to clarifying cannabis’ role in medicine

That currently there is limited or no evidence to support the use of medical cannabis for the treatment of neuropsychiatric conditions points to the inherent difficulties in conducting high-level research in this area.

“There’s a tremendous shortage of reliable data, largely due to regulatory barriers,” said Dr. Martinez.

Since 1970, cannabis has been listed as a Schedule I drug that is illegal to prescribe (the Agriculture Improvement Act of 2018 removed hemp from such restrictions). The FDA has issued guidance for researchers who wish to investigate treatments using Cannabis sativa or its derivatives in which the THC content is greater than 0.3%. Such research requires regular interactions with several federal agencies, including the Drug Enforcement Administration.

“It’s impossible to do multicenter RCTs with large numbers of patients, because you can’t transport cannabis across state lines,” said Dr. Wallace.

Regulatory restrictions regarding medical cannabis vary considerably throughout the world (the European Monitoring Center for Drugs and Drug Addiction provides a useful breakdown of this on their website). The lack of consistency in regulatory oversight acts as an impediment for conducting large-scale international multicenter studies on the topic.

Dr. Buhmann noted that, in Germany, cannabis has been broadly approved for treatment-resistant conditions with severe symptoms that impair quality of life. In addition, it is easy to be reimbursed for the use of cannabis as a medical treatment. These factors serve as disincentives for the funding of high-quality studies.

“It’s likely that no pharmaceutical company will do an expensive RCT to get an approval for Parkinson’s disease because it is already possible to prescribe medical cannabis of any type of THC-containing cannabinoid, dose, or route of application,” Dr. Buhmann said.

In the face of such restrictions and barriers, researchers are turning to ambitious real-world data projects to better understand medical cannabis’ efficacy and safety. A notable example is ProjectTwenty21, which is supported by the Royal College of Psychiatrists. The project is collecting outcomes of the use of medical cannabis among 20,000 U.K. patients whose conventional treatments of chronic pain, anxiety disorder, epilepsy, multiple sclerosis, PTSD, substance use disorder, and Tourette syndrome failed.

Dr. Freedman noted that the continued lack of high-quality data creates a void that commercial interests fill with unfounded claims.

“The danger is that patients might abandon a medication or intervention backed by robust science in favor of something without any science or evidence behind it,” he said. “There is no reason not to expect the same level of data for claims about cannabis products as we would expect from pharmaceutical products.”

Getting to that point, however, will require that the authorities governing clinical trials begin to view cannabis as the research community does, as a possible treatment with potential value, rather than as an illicit drug that needs to be tamped down.

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

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien

Against the backdrop of an increasing opioid use epidemic and a marked acceleration of prescription opioid–related deaths,^1,2 there has been an impetus to explore the usefulness of alternative and co-analgesic agents to assist patients with chronic pain. Preclinical studies employing animal-based models of human pain syndromes have demonstrated that cannabis and chemicals derived from cannabis extracts may mitigate several pain conditions.³

Because there are significant comorbidities between psychiatric disorders and chronic pain, psychiatrists are likely to care for patients with chronic pain. As the availability of and interest in cannabinoid-based medications (CBM) increases, psychiatrists will need to be apprised of the utility, adverse effects, and potential drug interactions of these agents.

The endocannabinoid system and cannabis receptors

The endogenous cannabinoid (endocannabinoid) system is abundantly present within the peripheral and central nervous systems. The first identified, and best studied, endocannabinoids are N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-arachidonoylglycerol (2-AG).⁴ Unlike typical neurotransmitters, AEA and 2-AG are not stored within vesicles within presynaptic neuron axons. Instead, they are lipophilic molecules produced on demand, synthesized from phospholipids (ie, arachidonic acid derivatives) at the membranes of post-synaptic neurons, and released into the synapse directly.⁵

Acting as retrograde messengers, the endocannabinoids traverse the synapse, binding to receptors located on the axons of the presynaptic neuron. Two receptors—CB1 and CB2—have been most extensively studied and characterized.^6,7 These receptors couple to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca2+ conductance and increasing K+ conductance.⁸ Once activated, cannabinoid receptors modulate neurotransmitter release from presynaptic axon terminals. Evidence points to a similar retrograde signaling between neurons and glial cells. Shortly after receptor activation, the endocannabinoids are deactivated by the actions of a transporter mechanism and enzyme degradation.^9,10

The endocannabinoid system and pain transmission

Cannabinoid receptors are present in pain transmission circuits spanning from the peripheral sensory nerve endings (from which pain signals originate) to the spinal cord and supraspinal regions within the brain.^11-14 CB1 receptors are abundantly present within the CNS, including regions involved in pain transmission. Binding to CB1 receptors, endocannabinoids modulate neurotransmission that impacts pain transmission centrally. Endocannabinoids can also indirectly modulate opiate and N-methyl-d-aspartate (NMDA) receptors involved in pain relay and transmission.¹⁵

By contrast, CB2 receptors are predominantly localized to peripheral tissues and immune cells, although there has been some discovery of their presence within the CNS (eg, on microglia). Endocannabinoid activation of CB2 receptors is thought to modulate the activity of peripheral afferent pain fibers and immune-mediated neuro­inflammatory processes—such as inhibition of prostaglandin synthesis and mast cell degranulation—that can precipitate and maintain chronic pain states.^16-18

Evidence garnered from preclinical (animal) studies points to the role of the endocannabinoid system in modulating normal pain transmission (see Manzanares et al³ for details). These studies offer a putative basis for understanding how exogenous cannabinoid congeners might serve to ameliorate pain transmission in pathophysiologic states, including chronic pain.

Continue to: Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psycho­active effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³ To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Neuropathic pain. Randomized controlled trials have assessed the pain-mitigating effects of various CBM, including inhaled cannabis, synthetic THC, plant-extracted CBD, and a THC/CBD spray. Studies have shown that inhaled/vaporized cannabis can produce short-term pain reduction in patients with chronic neuropathic pain of diverse etiologies, including diabetes mellitus-, HIV-, trauma-, and medication-induced neuropathies.^22,25,26 Similar beneficial effects have been observed with the use of cannabis analogues (eg, nabiximols).^25,26-29

Meta-analyses and systematic reviews have determined that most of these RCTs were of low-to-moderate quality.^26,30 Meta-analyses have revealed divergent and conflicting results because of differences in the inclusion and exclusion criteria used to select RCTs for analysis and differences in the standards with which the quality of evidence were determined.^25,30

Overall, the benefit of CBM for mitigating neuropathic pain is promising, but the effectiveness may not be robust.^30,31 Several noteworthy caveats limit the interpretation of the results of these RCTs:

• due to the small sample sizes and brief durations of study, questions remain regarding the extent to which effects are generalizable, whether the benefits are sustained, and whether adverse effects emerge over time with continued use
• most RCTs evaluated inhaled (herbal) cannabis and nabiximols; there is little data on the effectiveness of other CBM formulations^25,26,30
• the pain-mitigating effects of CBM were usually compared with those of placebo; the comparative efficacy against agents commonly used to treat neuropathic pain remains largely unexamined 

• these RCTs typically compared mean pain severity score differences between cannabis-treated and placebo groups using standard subjective rating scales of pain intensity, such as the Numerical Rating Scale or Visual Analogue Scale. Customarily, the pain literature has used a 30% or 50% reduction in pain severity from baseline as an indicator of significant clinical improvement.^32,33 The RCTs of CBM for neuropathic pain rarely used this standard, which makes it unclear whether CBM results in clinically significant pain reductions³⁰
• indirect measures of effectiveness (ie, whether using CBM reduces the need for opioids or other analgesics to manage pain) were seldom reported in these RCTs.

Due to these limitations, clinical guidelines and systematic reviews consider CBM as a third- or fourth-line therapy for patients experiencing chronic neuropathic pain for whom conventional agents such as anticonvulsants and antidepressants have failed.^34,35

Spasticity in multiple sclerosis (MS). Several RCTs have assessed the use of CBM for MS-related spasticity, although few were deemed to be high quality. Nabiximols and synthetic THC were effective in managing spasticity and reducing pain severity associated with muscle spasms.³⁶ Generally, investigations revealed that CBM were associated with improvements in subjective measures of spasticity, but these were not born out in clinical, objective measures.^26,37 The efficacy of smoked cannabis was uncertain.³⁷ The existing literature on CBM for MS-related spasticity does not address dosing, duration of effects, tolerability, or comparative effectiveness against conventional anti-spasm medications.^36,37

Continue to: Other chronic pain conditions

Other chronic pain conditions. CBM have also been studied for their usefulness in several other noncancer chronic conditions, including Crohn’s disease, inflammatory bowel disease, fibromyalgia, and other rheumatologic pain conditions.^22,31,38-40 However, a solid foundation of empirical work to inform their utility for managing pain in these conditions is lacking.

CBM for cancer pain

Anecdotal evidence suggests that inhaled cannabis has promising pain-mitigating effects in patients with advanced cancer.^41-43 There is a dearth of high-quality RCTs assessing the utility of CBM in patients with cancer pain.^43-45 The types of CBM used and dosing strategies varied across RCTs, which makes it difficult to infer how best to treat patients with cancer pain. The agents studied included nabiximols, THC spray, and synthetic THC capsules.^43-45 Although some studies have demonstrated that synthetic THC and nabiximols have potential for reducing subjective pain ratings compared with placebo,^46,47 these results were inconsistent.^46,48 Oromucosal nabiximols did not appear to confer any additional analgesic benefit in patients who were already prescribed opioids.^31,45

The benefit of CBM for mitigating cancer pain is promising, but it remains difficult to know how to position the use of CBM in managing cancer pain. Limitations in the cancer literature include:

• the RCTs addressing CBM use for cancer pain were often brief, which raises questions about the long-term effectiveness and adverse effects of these agents
• tolerability and dosing limits encountered due to adverse effects were seldom reported^43,45
• the types of cancer pain that patients had were often quite diverse. The small sample sizes and the heterogeneity of conditions included in these RCTs limit the ability to determine whether pain-mitigating effects might vary according to type of cancer-related pain.^31,45

Despite these limitations, some clinical guidelines and systematic reviews have suggested that CBM have some role in addressing refractory malignant pain conditions.⁴⁹

Psychiatric considerations related to CBM

As of November 2020, 36 states had legalized the use of cannabis for medical purposes, typically for painful conditions, despite the fact that empirical evidence to support their efficacy is mixed.⁵⁰ In light of recent changes in both the legal and popular attitudes regarding cannabis, the implications of legalizing CBM remains to be seen. For example, some research suggests that adults with pain are vulnerable to frequent nonmedical cannabis use and/or cannabis use disorder.⁵¹ Although well-intended, the legalization of CBM use might represent society’s next misstep in the quest to address the suffering of patients with chronic pain. Some evidence shows that cannabis use and cannabis use disorders increase in states that have legalized medical marijuana.^52,53 Psychiatrists will be on the front lines of addressing any potential consequences arising from the use of CBM for treating pain.

Continue to: Psychiatric disorders and CBM

Psychiatric disorders and CBM. The psychological impact of CBM use among patients enduring chronic pain can include sedation, cognitive/attention disturbance, and fatigue. These adverse effects can limit the utility of such agents.^22,29,45

Contraindications for CBM use, and conditions for which CBM ought to be used with caution, are listed in Table 3^54,55.The safety of CBM, particularly in patients with chronic pain and psychiatric disorders, has not been examined. Patients with psychiatric disorders may be poor candidates for medical cannabis. Epidemiologic data suggest that recreational cannabis use is positively associated both cross-sectionally and prospectively with psychotic spectrum disorders, depressive symptoms, and anxiety symptoms, including panic disorder.⁵⁶ Psychotic reactions have also been associated with CBM (dronabinol and nabilone).⁵⁷ Cannabis use also has been associated with an earlier onset of, and lower remission rates of, symptoms associated with bipolar disorder.^58,59 Consequently, patients who have been diagnosed with or are at risk for developing any of the aforementioned conditions may not be suitable candidates for CBM. If CBM are used, patients should be closely monitored for the emergence/exacerbation of psychiatric symptoms. The frequency and extent of follow-up is not clear, however. Because of its reduced propensity to produce psychoactive effects, CBD may be safer than THC for managing pain in individuals who have or are vulnerable to developing psychiatric disorders.

There is a lack of evidence to support the use of CBM for treating primary depressive disorders, general anxiety disorder, posttraumatic stress disorder, or psychosis.^60,61 Very low-quality evidence suggests that CBM could lead to a small improvement in anxiety among individuals with noncancer pain and MS.⁶⁰ However, interpreting causality is complicated. It is plausible that, for some patients, subjective improvement in pain severity may be related to reduced anxiety.⁶² Conversely, it is equally plausible that reductions in emotional distress may reduce the propensity to attend to, and thus magnify, pain severity. In the latter case, the indirect impact of reducing pain by modifying emotional distress can be impacted by the type and dose of CBM used. For example, low concentrations of THC produce anxiolytic effects, but high concentrations may be anxiety-provoking.^63,64

Several potential pharmacokinetic drug interactions may arise between herbal cannabis or CBM and other medications (Table 4^65,66). THC and CBD are both metabolized by cytochrome P450 (CYP) 2C19 and 3A4.^65,66 In addition, THC is also metabolized by CYP2C9. Medications that inhibit or induce these enzymes can increase or decrease the bioavailability of THC and CBD.⁶⁷

Simultaneously, cannabinoids can impact the bioavailability of co-prescribed medications (Table 5^66,68). Although such CYP enzyme interactions remain a theoretical possibility, it is uncertain whether significant perturbations in plasma concentrations (and clinical effects) have been encountered with prescription medications when co-administered with CBM.⁶⁹ Nonetheless, patients receiving CBM should be closely monitored for their response to prescribed medications.⁷⁰

Continue to: Potential CYP enzyme interactions...

Potential CYP enzyme interactions aside, clinicians need to consider the additive effects that may occur when CBM are combined with sympathomimetic agents (eg, tachycardia, hypertension); CNS depressants such as alcohol, benzodiazepines, and opioids (eg, drowsiness, ataxia); or anticholinergics (eg, tachycardia, confusion).⁷¹ Inhaled herbal cannabis contains mutagens and can result in lung damage, exacerbations of chronic bronchitis, and certain types of cancer.^54,72 Co-prescribing benzodiazepines may be contraindicated in light of their effects on respiratory rate and effort.

The THC contained in CBM produces hormonal effects (ie, significantly increases plasma levels of ghrelin and leptin and decreases peptide YY levels)⁷³ that affect appetite and can produce weight gain. This may be problematic for patients receiving psychoactive medications associated with increased risk of weight gain and dyslipidemia. Because of the association between cannabis use and motor vehicle accidents, patients whose jobs require them to drive or operate industrial equipment may not be ideal candidates for CBM, especially if such patients also consume alcohol or are prescribed benzodiazepines and/or sedative hypnotics.⁷⁴ Lastly, due to their lipophilicity, cannabinoids cross the placental barrier and can be found in breast milk⁷⁵ and therefore can affect pregnancy outcomes and neurodevelopment.

Bottom Line

The popularity of cannabinoid-based medications (CBM) for the treatment of chronic pain conditions is growing, but the interest in their use may be outpacing the evidence supporting their analgesic benefits. High-quality, well-controlled randomized controlled trials are needed to decipher whether, and to what extent, these agents can be positioned in chronic pain management. Because psychiatrists are likely to encounter patients considering, or receiving, CBM, they must be aware of the potential benefits, risks, and adverse effects of such treatments.

Related Resources

• Joshi KG. Cannabis-derived compounds: what you need to know. Current Psychiatry. 2020;19(10):64-65. doi:10.12788/ cp.0050
• Gupta S, Phalen T, Gupta S. Medical marijuana: do the benefits outweigh the risks? Current Psychiatry. 2018; 17(1):34-41.

Drug Brand Names

Ajulemic acid • Anabasum
Alprazolam • Xanax
Amitriptyline • Elavil
Aripiprazole • Abilify, Abilify Maintena
Buspirone • BuSpar
Cannabidiol • Epidiolex
Carbamazepine • Tegretol, Equetro
Cimetidine • Tagamet HB
Citalopram • Celexa
Clopidogrel • Plavix
Clozapine • Clozaril
Cyclosporine • Neoral, Sandimmune
Dronabinol • Marinol, Syndros
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Ketoconazole • Nizoral AD
Losartan • Cozaar
Midazolam • Versed
Mirtazapine • Remeron
Nabilone • Cesamet
Nabiximols • Sativex
Nefazodone • Serzone
Olanzapine • Zyprexa
Phenobarbital • Solfoton
Phenytoin • Dilantin
Ramelteon • Rozerem
Rifampin • Rifadin
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Topiramate • Topamax
Valproic acid • Depakote, Depakene
Venlafaxine • Effexor
Verapamil • Verelan
Zolpidem • Ambien