ABSTRACT

BACKGROUND: Historically, nebulizers have been preferred over metered-dose inhalers (MDIs) for the treatment of asthma exacerbations, although numerous studies have shown their equivalence. A systematic review of 21 randomized trials supported the equivalence of an MDI with spacer and a nebulizer; the method of albuterol delivery did not affect hospital admission rates, length of stay in the emergency department, or measures of pulmonary function.¹ Advantages of MDIs may include lower costs, less excess drug exposure, and easier use for patients and physicians.

POPULATION STUDIED: The study population consisted of all patients older than 18 years who presented to an emergency department over a 2.5-year period with an asthma exacerbation (2342 visits, 1429 patients). Most patients were African American (75.4%). Most were women (58.6%), and the mean age was 35.5 ± 13.5 years.

STUDY DESIGN AND VALIDITY: The study was a large, prospective, unblinded, and nonrandomized trial consisting of 2 phases. For the first 12 months, physicians, using standard National Institues of Health guidelines, began treatment with a nebulizer (913 visits). Then for the next 18 months, physicians began treatment with albuterol delivered via MDI and spacer (1429 visits). The dose was 5 puffs, then 3 to 5 puffs every 20 minutes as needed. At the time of discharge from the emergency department during the MDI phase of the study, patients received a peak flow meter, an MDI and spacer, an inhaled corticosteroid, written materials, and counseling by emergency department nurses.

OUTCOMES MEASURED: The outcomes measured were PEFR, Sao ₂, heart and respiratory rates, total albuterol dose, and the more patient-oriented outcomes of rate of hospital admission, relapse rate, time in the emergency department, and costs.

RESULTS: In the MDI phase, post-albuterol PEFR was 11.0% higher (342 L/min vs 308 L/min; P = .001) and change in PEFR was 13.3% higher (127 L/min vs 112 L/min; P = .002). Change in Sao ₂ was significant (P = .043), and the total albuterol dose was significantly less in the MDI group (1125 μg vs 6700 μg; P = .001). However, these differences did not result in significantly lower hospital admission rates. Relapse rates were significantly lower at both 14 and 21 days in the MDI phase (6.6% and 10.7% vs 9.6% and 13.5%; P < .01 and P < .05). Patients treated with MDIs spent 6.5% less time in the emergency department (163.6 min vs 175.0 min; P = .007). The difference in visit charges was not significant.

ABSTRACT

BACKGROUND: Historically, nebulizers have been preferred over metered-dose inhalers (MDIs) for the treatment of asthma exacerbations, although numerous studies have shown their equivalence. A systematic review of 21 randomized trials supported the equivalence of an MDI with spacer and a nebulizer; the method of albuterol delivery did not affect hospital admission rates, length of stay in the emergency department, or measures of pulmonary function.¹ Advantages of MDIs may include lower costs, less excess drug exposure, and easier use for patients and physicians.

POPULATION STUDIED: The study population consisted of all patients older than 18 years who presented to an emergency department over a 2.5-year period with an asthma exacerbation (2342 visits, 1429 patients). Most patients were African American (75.4%). Most were women (58.6%), and the mean age was 35.5 ± 13.5 years.

STUDY DESIGN AND VALIDITY: The study was a large, prospective, unblinded, and nonrandomized trial consisting of 2 phases. For the first 12 months, physicians, using standard National Institues of Health guidelines, began treatment with a nebulizer (913 visits). Then for the next 18 months, physicians began treatment with albuterol delivered via MDI and spacer (1429 visits). The dose was 5 puffs, then 3 to 5 puffs every 20 minutes as needed. At the time of discharge from the emergency department during the MDI phase of the study, patients received a peak flow meter, an MDI and spacer, an inhaled corticosteroid, written materials, and counseling by emergency department nurses.

OUTCOMES MEASURED: The outcomes measured were PEFR, Sao ₂, heart and respiratory rates, total albuterol dose, and the more patient-oriented outcomes of rate of hospital admission, relapse rate, time in the emergency department, and costs.

RESULTS: In the MDI phase, post-albuterol PEFR was 11.0% higher (342 L/min vs 308 L/min; P = .001) and change in PEFR was 13.3% higher (127 L/min vs 112 L/min; P = .002). Change in Sao ₂ was significant (P = .043), and the total albuterol dose was significantly less in the MDI group (1125 μg vs 6700 μg; P = .001). However, these differences did not result in significantly lower hospital admission rates. Relapse rates were significantly lower at both 14 and 21 days in the MDI phase (6.6% and 10.7% vs 9.6% and 13.5%; P < .01 and P < .05). Patients treated with MDIs spent 6.5% less time in the emergency department (163.6 min vs 175.0 min; P = .007). The difference in visit charges was not significant.

ABSTRACT

BACKGROUND: Historically, nebulizers have been preferred over metered-dose inhalers (MDIs) for the treatment of asthma exacerbations, although numerous studies have shown their equivalence. A systematic review of 21 randomized trials supported the equivalence of an MDI with spacer and a nebulizer; the method of albuterol delivery did not affect hospital admission rates, length of stay in the emergency department, or measures of pulmonary function.¹ Advantages of MDIs may include lower costs, less excess drug exposure, and easier use for patients and physicians.

POPULATION STUDIED: The study population consisted of all patients older than 18 years who presented to an emergency department over a 2.5-year period with an asthma exacerbation (2342 visits, 1429 patients). Most patients were African American (75.4%). Most were women (58.6%), and the mean age was 35.5 ± 13.5 years.

STUDY DESIGN AND VALIDITY: The study was a large, prospective, unblinded, and nonrandomized trial consisting of 2 phases. For the first 12 months, physicians, using standard National Institues of Health guidelines, began treatment with a nebulizer (913 visits). Then for the next 18 months, physicians began treatment with albuterol delivered via MDI and spacer (1429 visits). The dose was 5 puffs, then 3 to 5 puffs every 20 minutes as needed. At the time of discharge from the emergency department during the MDI phase of the study, patients received a peak flow meter, an MDI and spacer, an inhaled corticosteroid, written materials, and counseling by emergency department nurses.

OUTCOMES MEASURED: The outcomes measured were PEFR, Sao ₂, heart and respiratory rates, total albuterol dose, and the more patient-oriented outcomes of rate of hospital admission, relapse rate, time in the emergency department, and costs.

RESULTS: In the MDI phase, post-albuterol PEFR was 11.0% higher (342 L/min vs 308 L/min; P = .001) and change in PEFR was 13.3% higher (127 L/min vs 112 L/min; P = .002). Change in Sao ₂ was significant (P = .043), and the total albuterol dose was significantly less in the MDI group (1125 μg vs 6700 μg; P = .001). However, these differences did not result in significantly lower hospital admission rates. Relapse rates were significantly lower at both 14 and 21 days in the MDI phase (6.6% and 10.7% vs 9.6% and 13.5%; P < .01 and P < .05). Patients treated with MDIs spent 6.5% less time in the emergency department (163.6 min vs 175.0 min; P = .007). The difference in visit charges was not significant.

ABSTRACT

BACKGROUND: Bolus intravenous (IV) albuterol (salbutamol) improved outcomes in pediatric patients with severe asthma exacerbations in 1 earlier small study. Previous studies demonstrated that the addition of nebulized ipratropium bromide to initial emergency department therapy improves pulmonary function, but it is unclear whether combining the therapies results in earlier hospital discharge. This study compared these 2 approaches to determine their relative benefit in children with acute severe asthma.

POPULATION STUDIED: The researchers studied 55 children (aged 1–14 years) presenting with severe acute asthma to the emergency department of a ter-tiary children’s hospital in Sydney, Australia. Children were classified as having severe asthma if they had all 4 features of respiratory distress (wheezing, sternal retraction, accessory muscle use, and dyspnea) or had any of the absolute criteria (cyanosis, pulsus paradoxus, altered consciousness, or a silent chest auscultation). Baseline demographics and clinical characteristics were similar. Children who were excluded included those with life-threatening asthma, age younger than 12 months, presence of heart disease, family history of Wolff-Parkinson-White or past supraventricular tachycardia, other respiratory disease, or pneumonia, and those who had received inhaled ipratropium bromide that day.

STUDY DESIGN AND VALIDITY: This was a randomized, double-blind, double-dummy trial. The enrolling physician, treating physician, and assessor of outcome were all blinded. All children received 1 dose of nebulized albuterol 2.5 or 5 mg, then were assessed for asthma severity. Children meeting inclusion criteria received oxygen as needed, 1 mg/kg IV bolus methylprednisolone, and nebulized albuterol every 20 minutes for the first hour. The frequency of nebulized albuterol was then decreased based on clinical improvement. Patients were then randomized to receive IV albuterol (15 μg/kg); IV saline and inhaled ipratropium bromide (250 mg) every 20 minutes; or IV albuterol (15 μg/kg) and inhaled ipratropium bromide (250 μg) every 20 minutes. Asthma severity was assessed at 1 and 2 hours into the study using the clinical assessment scale and pulmonary index score. All 55 children completed the study.

OUTCOMES MEASURED: The primary outcomes for this study were mean recovery time (time from randomization to when patients no longer needed nebulized albuterol of a given frequency) and mean discharge time from the hospital. Secondary outcomes included clinical signs of moderate to severe asthma 2 hours after randomization and incidence of medication-related side effects.

RESULTS: Children treated with IV albuterol showed a significant benefit over those treated with inhaled ipratropium in recovery at 90, 120, and 180 minutes (P = .007, .01, and .004, respectively). Children in the IV albuterol group were ready for discharge 28.0 hours earlier than those in the ipratropium group (48.3 vs 76.3 hours; P = .005). The combination of IV albuterol and ipratropium showed a significant benefit over ipratropium alone in recovery time at 90 and 120 minutes (P = .02 and .008, respectively). However, no significant difference was evident between the combination and ipratropium alone in time to discharge (57.6 vs 76.3 hours, respectively; P = .2). The combination demonstrated no significant benefit over IV albuterol for any outcome. No significant adverse effects were documented in any of the patients, including tachycardia of more than 200 beats per minute for at least 5 minutes.

ABSTRACT

BACKGROUND: Bolus intravenous (IV) albuterol (salbutamol) improved outcomes in pediatric patients with severe asthma exacerbations in 1 earlier small study. Previous studies demonstrated that the addition of nebulized ipratropium bromide to initial emergency department therapy improves pulmonary function, but it is unclear whether combining the therapies results in earlier hospital discharge. This study compared these 2 approaches to determine their relative benefit in children with acute severe asthma.

POPULATION STUDIED: The researchers studied 55 children (aged 1–14 years) presenting with severe acute asthma to the emergency department of a ter-tiary children’s hospital in Sydney, Australia. Children were classified as having severe asthma if they had all 4 features of respiratory distress (wheezing, sternal retraction, accessory muscle use, and dyspnea) or had any of the absolute criteria (cyanosis, pulsus paradoxus, altered consciousness, or a silent chest auscultation). Baseline demographics and clinical characteristics were similar. Children who were excluded included those with life-threatening asthma, age younger than 12 months, presence of heart disease, family history of Wolff-Parkinson-White or past supraventricular tachycardia, other respiratory disease, or pneumonia, and those who had received inhaled ipratropium bromide that day.

STUDY DESIGN AND VALIDITY: This was a randomized, double-blind, double-dummy trial. The enrolling physician, treating physician, and assessor of outcome were all blinded. All children received 1 dose of nebulized albuterol 2.5 or 5 mg, then were assessed for asthma severity. Children meeting inclusion criteria received oxygen as needed, 1 mg/kg IV bolus methylprednisolone, and nebulized albuterol every 20 minutes for the first hour. The frequency of nebulized albuterol was then decreased based on clinical improvement. Patients were then randomized to receive IV albuterol (15 μg/kg); IV saline and inhaled ipratropium bromide (250 mg) every 20 minutes; or IV albuterol (15 μg/kg) and inhaled ipratropium bromide (250 μg) every 20 minutes. Asthma severity was assessed at 1 and 2 hours into the study using the clinical assessment scale and pulmonary index score. All 55 children completed the study.

OUTCOMES MEASURED: The primary outcomes for this study were mean recovery time (time from randomization to when patients no longer needed nebulized albuterol of a given frequency) and mean discharge time from the hospital. Secondary outcomes included clinical signs of moderate to severe asthma 2 hours after randomization and incidence of medication-related side effects.

RESULTS: Children treated with IV albuterol showed a significant benefit over those treated with inhaled ipratropium in recovery at 90, 120, and 180 minutes (P = .007, .01, and .004, respectively). Children in the IV albuterol group were ready for discharge 28.0 hours earlier than those in the ipratropium group (48.3 vs 76.3 hours; P = .005). The combination of IV albuterol and ipratropium showed a significant benefit over ipratropium alone in recovery time at 90 and 120 minutes (P = .02 and .008, respectively). However, no significant difference was evident between the combination and ipratropium alone in time to discharge (57.6 vs 76.3 hours, respectively; P = .2). The combination demonstrated no significant benefit over IV albuterol for any outcome. No significant adverse effects were documented in any of the patients, including tachycardia of more than 200 beats per minute for at least 5 minutes.

ABSTRACT

BACKGROUND: Bolus intravenous (IV) albuterol (salbutamol) improved outcomes in pediatric patients with severe asthma exacerbations in 1 earlier small study. Previous studies demonstrated that the addition of nebulized ipratropium bromide to initial emergency department therapy improves pulmonary function, but it is unclear whether combining the therapies results in earlier hospital discharge. This study compared these 2 approaches to determine their relative benefit in children with acute severe asthma.

POPULATION STUDIED: The researchers studied 55 children (aged 1–14 years) presenting with severe acute asthma to the emergency department of a ter-tiary children’s hospital in Sydney, Australia. Children were classified as having severe asthma if they had all 4 features of respiratory distress (wheezing, sternal retraction, accessory muscle use, and dyspnea) or had any of the absolute criteria (cyanosis, pulsus paradoxus, altered consciousness, or a silent chest auscultation). Baseline demographics and clinical characteristics were similar. Children who were excluded included those with life-threatening asthma, age younger than 12 months, presence of heart disease, family history of Wolff-Parkinson-White or past supraventricular tachycardia, other respiratory disease, or pneumonia, and those who had received inhaled ipratropium bromide that day.

STUDY DESIGN AND VALIDITY: This was a randomized, double-blind, double-dummy trial. The enrolling physician, treating physician, and assessor of outcome were all blinded. All children received 1 dose of nebulized albuterol 2.5 or 5 mg, then were assessed for asthma severity. Children meeting inclusion criteria received oxygen as needed, 1 mg/kg IV bolus methylprednisolone, and nebulized albuterol every 20 minutes for the first hour. The frequency of nebulized albuterol was then decreased based on clinical improvement. Patients were then randomized to receive IV albuterol (15 μg/kg); IV saline and inhaled ipratropium bromide (250 mg) every 20 minutes; or IV albuterol (15 μg/kg) and inhaled ipratropium bromide (250 μg) every 20 minutes. Asthma severity was assessed at 1 and 2 hours into the study using the clinical assessment scale and pulmonary index score. All 55 children completed the study.

OUTCOMES MEASURED: The primary outcomes for this study were mean recovery time (time from randomization to when patients no longer needed nebulized albuterol of a given frequency) and mean discharge time from the hospital. Secondary outcomes included clinical signs of moderate to severe asthma 2 hours after randomization and incidence of medication-related side effects.

RESULTS: Children treated with IV albuterol showed a significant benefit over those treated with inhaled ipratropium in recovery at 90, 120, and 180 minutes (P = .007, .01, and .004, respectively). Children in the IV albuterol group were ready for discharge 28.0 hours earlier than those in the ipratropium group (48.3 vs 76.3 hours; P = .005). The combination of IV albuterol and ipratropium showed a significant benefit over ipratropium alone in recovery time at 90 and 120 minutes (P = .02 and .008, respectively). However, no significant difference was evident between the combination and ipratropium alone in time to discharge (57.6 vs 76.3 hours, respectively; P = .2). The combination demonstrated no significant benefit over IV albuterol for any outcome. No significant adverse effects were documented in any of the patients, including tachycardia of more than 200 beats per minute for at least 5 minutes.

Evidence summary

Although several studies have shown the benefit of placing asthmatic and allergic children in highly sanitized hospital and sanitarium environments,¹ benefit has been extremely difficult to prove with measures used in the child’s home. Only reducing tobacco smoke exposure has been shown to be beneficial. In a randomized trial of predominantly poor minority subjects, fewer acute asthma medical visits were needed by children whose household members underwent behavioral education aimed at decreasing smoke exposure.²

Other methods of modifying the environment have not proved beneficial. Although a group of researchers found that home visits by care providers may decrease acute medical visits, specific allergy avoidance steps did not make a difference.³ Two of these authors also reported that the use of chemicals for house dust mite control and the use of synthetic pillows in lieu of feather pillows may actually exacerbate asthma.⁴ A Cochrane review was inconclusive on the risks or benefits of feather bedding.⁵ Benefit from removing cats is difficult to prove because of the ubiquitous nature of cat antigen and the difficulty in eradicating it from the home. Using air filters and reducing indoor humidity have likewise failed to show meaningful improvement in peak flow, medication use, or symptom scores.

The effectiveness of physical methods to reduce house dust mites is unclear. The Cochrane Review of 15 trials noted a small, statistically significant improvement in asthma symptom scores, but the results were not clinically important enough to recommend such measures.⁶ The potential harm of chemical measures was reiterated in this review.

TABLE
Environmental modifications for children with asthma

Recommendations from others

The National Heart, Lung, and Blood Institute continues to recommend physical barriers to reduce house dust mite antigen based on 4 small trials in which the major benefit was decreased bronchial hyperresponsiveness.⁷ Larger trials, now under way, may help resolve the issue.

Clinical Commentary by Nicholas J. Solomos, MD, at http://www.fpin.org.

Evidence summary

Although several studies have shown the benefit of placing asthmatic and allergic children in highly sanitized hospital and sanitarium environments,¹ benefit has been extremely difficult to prove with measures used in the child’s home. Only reducing tobacco smoke exposure has been shown to be beneficial. In a randomized trial of predominantly poor minority subjects, fewer acute asthma medical visits were needed by children whose household members underwent behavioral education aimed at decreasing smoke exposure.²

Other methods of modifying the environment have not proved beneficial. Although a group of researchers found that home visits by care providers may decrease acute medical visits, specific allergy avoidance steps did not make a difference.³ Two of these authors also reported that the use of chemicals for house dust mite control and the use of synthetic pillows in lieu of feather pillows may actually exacerbate asthma.⁴ A Cochrane review was inconclusive on the risks or benefits of feather bedding.⁵ Benefit from removing cats is difficult to prove because of the ubiquitous nature of cat antigen and the difficulty in eradicating it from the home. Using air filters and reducing indoor humidity have likewise failed to show meaningful improvement in peak flow, medication use, or symptom scores.

The effectiveness of physical methods to reduce house dust mites is unclear. The Cochrane Review of 15 trials noted a small, statistically significant improvement in asthma symptom scores, but the results were not clinically important enough to recommend such measures.⁶ The potential harm of chemical measures was reiterated in this review.

TABLE
Environmental modifications for children with asthma

Recommendations from others

The National Heart, Lung, and Blood Institute continues to recommend physical barriers to reduce house dust mite antigen based on 4 small trials in which the major benefit was decreased bronchial hyperresponsiveness.⁷ Larger trials, now under way, may help resolve the issue.

Clinical Commentary by Nicholas J. Solomos, MD, at http://www.fpin.org.

Evidence summary

Although several studies have shown the benefit of placing asthmatic and allergic children in highly sanitized hospital and sanitarium environments,¹ benefit has been extremely difficult to prove with measures used in the child’s home. Only reducing tobacco smoke exposure has been shown to be beneficial. In a randomized trial of predominantly poor minority subjects, fewer acute asthma medical visits were needed by children whose household members underwent behavioral education aimed at decreasing smoke exposure.²

Other methods of modifying the environment have not proved beneficial. Although a group of researchers found that home visits by care providers may decrease acute medical visits, specific allergy avoidance steps did not make a difference.³ Two of these authors also reported that the use of chemicals for house dust mite control and the use of synthetic pillows in lieu of feather pillows may actually exacerbate asthma.⁴ A Cochrane review was inconclusive on the risks or benefits of feather bedding.⁵ Benefit from removing cats is difficult to prove because of the ubiquitous nature of cat antigen and the difficulty in eradicating it from the home. Using air filters and reducing indoor humidity have likewise failed to show meaningful improvement in peak flow, medication use, or symptom scores.

The effectiveness of physical methods to reduce house dust mites is unclear. The Cochrane Review of 15 trials noted a small, statistically significant improvement in asthma symptom scores, but the results were not clinically important enough to recommend such measures.⁶ The potential harm of chemical measures was reiterated in this review.

TABLE
Environmental modifications for children with asthma

Recommendations from others

The National Heart, Lung, and Blood Institute continues to recommend physical barriers to reduce house dust mite antigen based on 4 small trials in which the major benefit was decreased bronchial hyperresponsiveness.⁷ Larger trials, now under way, may help resolve the issue.

Clinical Commentary by Nicholas J. Solomos, MD, at http://www.fpin.org.

Constipation is an often-overlooked problem in primary care practice. It deserves careful evaluation, including consideration of the many possible causes and appropriate diagnostic testing. Fortunately, most patients respond well to conservative measures.

Constipation prompts a visit to a physician by 1.2% of the US population every year (although most persons with constipation do not seek the assistance of a physician).^{What You Should Know About Constipation,” is included with this article. (For your convenience, it may be freely duplicated and distributed.)}

Suggested lifestyle changes include moderate physical activity, increased fluid intake, increased dietary fiber, and sitting on the toilet about 15–20 minutes after breakfast (taking advantage of the gastrocolic reflex). In selected patients, these changes may be useful, although specific benefits of moderate physical activity and increased fluid intake have not been conclusively proven.

Bulk laxatives

Wheat bran is one of the best and least expensive bulk laxatives. Methylcellulose (eg, Citrucel), psyllium (eg, Metamucil), and polycarbophil (eg, FiberCon) are bulk laxatives that are safe, more refined, and more concentrated than wheat bran, but they are also more expensive. Combined with diet and liquids, bulk laxatives are the most effective and “natural” long-term treatment for constipation. However, their slow onset of action (between 12 and 72 hours) limits their usefulness in acute management of constipation.

Saline laxatives

The saline laxatives include magnesium citrate (eg, Citroma) and magnesium hydroxide (eg, Milk of Magnesia). These agents decrease colonic transit time by stimulating cholecystokinin and draw fluid into the colon by their osmotic effect. Their rapid onset of action (between 30 minutes and 3 hours) makes saline laxatives an excellent choice for acute management of constipation. These laxatives commonly cause abdominal cramping and, in patients with renal failure, may cause magnesium toxicity. Nevertheless, saline laxatives are generally safe and effective.

Osmotic laxatives

Polyethylene glycol (eg, MiraLax) is an effective new osmotic laxative. Rapid onset of action (between 24 and 48 hours) makes an osmotic a good choice for patients who have chronic constipation that fails to respond to bulk and saline laxatives. Polyethylene glycol is equally effective, but better tolerated than the older osmotics, lactulose and sorbitol.¹⁶ Because it is not fermented, gas and cramps are minimal. Lactulose (eg, Chronulac) and sorbitol, which are poorly absorbed sugars, likewise have rapid onset of action, but flatulence and abdominal distention may limit tolerance. Sorbitol is generally less expensive than lactulose.

Stimulant laxatives

The oral stimulant laxatives include diphenylmethanes, the anthraquinones, and castor oil (eg, Emulsoil). They are more potent than bulk or osmotic laxatives, but long-term use is safe if limited to 3 days per week. Bisacodyl (eg, Dulcolax), a diphenylmethane, alters electrolyte transportation within intestinal mucosa and stimulates peristalsis. These actions may cause abdominal cramping and hypokalemia. Cascara (mildest), senna (eg, Senokot), and aloe (strongest) are anthraquinones, which are laxatives with actions and side effects similar to bisacodyl. These agents may cause a benign, reversible pigmentation of the colon (melanosis coli). It has been suggested that chronic use of these agents may damage the enteric nervous system, but a causal relationship has not been clearly established. The most prudent approach is to limit use of stimulant laxatives to constipation that is refractory to other laxatives.

Enemas and suppositories

Enemas and suppositories stimulate colonic contractions and soften stools. Water, saline, soap suds, hypertonic sodium phosphate, and mineral oil are used as enemas. Acute water intoxication can occur with water enemas, especially in infants, children, and the elderly, if they have difficulty evacuating the water. Phosphate enemas may cause hyperphosphatemia and hypocalcemic tetany in these patients and should therefore be used with caution in most patients and should not be used in children 3 years of age or younger. Glycerin and bisacodyl are stimulant suppositories that are clinically effective. Bisacodyl and soap suds enemas cause changes in the epithelium of the rectum, and the effect of glycerin on rectal mucosa is unclear. Therefore, these agents should only be used episodically. Mineral oil enemas are used to soften hardened stool in the rectal ampulla.

Other treatment options

More aggressive measures may be necessary for specific types of constipation. These include behavioral therapy and biofeedback for pelvic floor dysfunction, and surgery for slow-transit constipation or Hirschsprung’s disease.

Investigative pharmacologic treatments for constipation include agents that increase colonic contractions (prokinetic drugs) and prostaglandins. These agents have had limited efficacy and troublesome side effects. Therefore, at this time these drugs have limited usefulness in the treatment of constipation.

Fecal impaction

The management of fecal impaction begins with complete evacuation of the colon. Initially, patients with hard stool in the rectum may be given mineral oil retention enemas followed by manual disimpaction. Prior to further treatment, it is important to obtain an abdominal radiograph to rule out mechanical bowel obstruction. If there is no mechanical bowel obstruction, evacuation of the impaction can be accomplished with oral polyethylene glycol (eg, GoLytely) until clear (up to 8 liters or more may be required for complete evacuation).¹⁶ Administration of twice-daily enemas for 3 days or more is an acceptable alternative to oral polyethylene glycol. Lifestyle changes, bulk laxatives, saline, osmotic laxatives, and enemas should be used to maintain regular defecation after the colon has been cleansed. It is reasonable to attempt to withdraw laxatives after several months of regular bowel habits.

Constipation is an often-overlooked problem in primary care practice. It deserves careful evaluation, including consideration of the many possible causes and appropriate diagnostic testing. Fortunately, most patients respond well to conservative measures.

Constipation prompts a visit to a physician by 1.2% of the US population every year (although most persons with constipation do not seek the assistance of a physician).^{What You Should Know About Constipation,” is included with this article. (For your convenience, it may be freely duplicated and distributed.)}

Suggested lifestyle changes include moderate physical activity, increased fluid intake, increased dietary fiber, and sitting on the toilet about 15–20 minutes after breakfast (taking advantage of the gastrocolic reflex). In selected patients, these changes may be useful, although specific benefits of moderate physical activity and increased fluid intake have not been conclusively proven.

Bulk laxatives

Wheat bran is one of the best and least expensive bulk laxatives. Methylcellulose (eg, Citrucel), psyllium (eg, Metamucil), and polycarbophil (eg, FiberCon) are bulk laxatives that are safe, more refined, and more concentrated than wheat bran, but they are also more expensive. Combined with diet and liquids, bulk laxatives are the most effective and “natural” long-term treatment for constipation. However, their slow onset of action (between 12 and 72 hours) limits their usefulness in acute management of constipation.

Saline laxatives

The saline laxatives include magnesium citrate (eg, Citroma) and magnesium hydroxide (eg, Milk of Magnesia). These agents decrease colonic transit time by stimulating cholecystokinin and draw fluid into the colon by their osmotic effect. Their rapid onset of action (between 30 minutes and 3 hours) makes saline laxatives an excellent choice for acute management of constipation. These laxatives commonly cause abdominal cramping and, in patients with renal failure, may cause magnesium toxicity. Nevertheless, saline laxatives are generally safe and effective.

Osmotic laxatives

Polyethylene glycol (eg, MiraLax) is an effective new osmotic laxative. Rapid onset of action (between 24 and 48 hours) makes an osmotic a good choice for patients who have chronic constipation that fails to respond to bulk and saline laxatives. Polyethylene glycol is equally effective, but better tolerated than the older osmotics, lactulose and sorbitol.¹⁶ Because it is not fermented, gas and cramps are minimal. Lactulose (eg, Chronulac) and sorbitol, which are poorly absorbed sugars, likewise have rapid onset of action, but flatulence and abdominal distention may limit tolerance. Sorbitol is generally less expensive than lactulose.

Stimulant laxatives

The oral stimulant laxatives include diphenylmethanes, the anthraquinones, and castor oil (eg, Emulsoil). They are more potent than bulk or osmotic laxatives, but long-term use is safe if limited to 3 days per week. Bisacodyl (eg, Dulcolax), a diphenylmethane, alters electrolyte transportation within intestinal mucosa and stimulates peristalsis. These actions may cause abdominal cramping and hypokalemia. Cascara (mildest), senna (eg, Senokot), and aloe (strongest) are anthraquinones, which are laxatives with actions and side effects similar to bisacodyl. These agents may cause a benign, reversible pigmentation of the colon (melanosis coli). It has been suggested that chronic use of these agents may damage the enteric nervous system, but a causal relationship has not been clearly established. The most prudent approach is to limit use of stimulant laxatives to constipation that is refractory to other laxatives.

Enemas and suppositories

Enemas and suppositories stimulate colonic contractions and soften stools. Water, saline, soap suds, hypertonic sodium phosphate, and mineral oil are used as enemas. Acute water intoxication can occur with water enemas, especially in infants, children, and the elderly, if they have difficulty evacuating the water. Phosphate enemas may cause hyperphosphatemia and hypocalcemic tetany in these patients and should therefore be used with caution in most patients and should not be used in children 3 years of age or younger. Glycerin and bisacodyl are stimulant suppositories that are clinically effective. Bisacodyl and soap suds enemas cause changes in the epithelium of the rectum, and the effect of glycerin on rectal mucosa is unclear. Therefore, these agents should only be used episodically. Mineral oil enemas are used to soften hardened stool in the rectal ampulla.

Other treatment options

More aggressive measures may be necessary for specific types of constipation. These include behavioral therapy and biofeedback for pelvic floor dysfunction, and surgery for slow-transit constipation or Hirschsprung’s disease.

Investigative pharmacologic treatments for constipation include agents that increase colonic contractions (prokinetic drugs) and prostaglandins. These agents have had limited efficacy and troublesome side effects. Therefore, at this time these drugs have limited usefulness in the treatment of constipation.

Fecal impaction

The management of fecal impaction begins with complete evacuation of the colon. Initially, patients with hard stool in the rectum may be given mineral oil retention enemas followed by manual disimpaction. Prior to further treatment, it is important to obtain an abdominal radiograph to rule out mechanical bowel obstruction. If there is no mechanical bowel obstruction, evacuation of the impaction can be accomplished with oral polyethylene glycol (eg, GoLytely) until clear (up to 8 liters or more may be required for complete evacuation).¹⁶ Administration of twice-daily enemas for 3 days or more is an acceptable alternative to oral polyethylene glycol. Lifestyle changes, bulk laxatives, saline, osmotic laxatives, and enemas should be used to maintain regular defecation after the colon has been cleansed. It is reasonable to attempt to withdraw laxatives after several months of regular bowel habits.

Constipation is an often-overlooked problem in primary care practice. It deserves careful evaluation, including consideration of the many possible causes and appropriate diagnostic testing. Fortunately, most patients respond well to conservative measures.

Constipation prompts a visit to a physician by 1.2% of the US population every year (although most persons with constipation do not seek the assistance of a physician).^{What You Should Know About Constipation,” is included with this article. (For your convenience, it may be freely duplicated and distributed.)}

Suggested lifestyle changes include moderate physical activity, increased fluid intake, increased dietary fiber, and sitting on the toilet about 15–20 minutes after breakfast (taking advantage of the gastrocolic reflex). In selected patients, these changes may be useful, although specific benefits of moderate physical activity and increased fluid intake have not been conclusively proven.

Bulk laxatives

Wheat bran is one of the best and least expensive bulk laxatives. Methylcellulose (eg, Citrucel), psyllium (eg, Metamucil), and polycarbophil (eg, FiberCon) are bulk laxatives that are safe, more refined, and more concentrated than wheat bran, but they are also more expensive. Combined with diet and liquids, bulk laxatives are the most effective and “natural” long-term treatment for constipation. However, their slow onset of action (between 12 and 72 hours) limits their usefulness in acute management of constipation.

Saline laxatives

The saline laxatives include magnesium citrate (eg, Citroma) and magnesium hydroxide (eg, Milk of Magnesia). These agents decrease colonic transit time by stimulating cholecystokinin and draw fluid into the colon by their osmotic effect. Their rapid onset of action (between 30 minutes and 3 hours) makes saline laxatives an excellent choice for acute management of constipation. These laxatives commonly cause abdominal cramping and, in patients with renal failure, may cause magnesium toxicity. Nevertheless, saline laxatives are generally safe and effective.

Osmotic laxatives

Polyethylene glycol (eg, MiraLax) is an effective new osmotic laxative. Rapid onset of action (between 24 and 48 hours) makes an osmotic a good choice for patients who have chronic constipation that fails to respond to bulk and saline laxatives. Polyethylene glycol is equally effective, but better tolerated than the older osmotics, lactulose and sorbitol.¹⁶ Because it is not fermented, gas and cramps are minimal. Lactulose (eg, Chronulac) and sorbitol, which are poorly absorbed sugars, likewise have rapid onset of action, but flatulence and abdominal distention may limit tolerance. Sorbitol is generally less expensive than lactulose.

Stimulant laxatives

The oral stimulant laxatives include diphenylmethanes, the anthraquinones, and castor oil (eg, Emulsoil). They are more potent than bulk or osmotic laxatives, but long-term use is safe if limited to 3 days per week. Bisacodyl (eg, Dulcolax), a diphenylmethane, alters electrolyte transportation within intestinal mucosa and stimulates peristalsis. These actions may cause abdominal cramping and hypokalemia. Cascara (mildest), senna (eg, Senokot), and aloe (strongest) are anthraquinones, which are laxatives with actions and side effects similar to bisacodyl. These agents may cause a benign, reversible pigmentation of the colon (melanosis coli). It has been suggested that chronic use of these agents may damage the enteric nervous system, but a causal relationship has not been clearly established. The most prudent approach is to limit use of stimulant laxatives to constipation that is refractory to other laxatives.

Enemas and suppositories

Enemas and suppositories stimulate colonic contractions and soften stools. Water, saline, soap suds, hypertonic sodium phosphate, and mineral oil are used as enemas. Acute water intoxication can occur with water enemas, especially in infants, children, and the elderly, if they have difficulty evacuating the water. Phosphate enemas may cause hyperphosphatemia and hypocalcemic tetany in these patients and should therefore be used with caution in most patients and should not be used in children 3 years of age or younger. Glycerin and bisacodyl are stimulant suppositories that are clinically effective. Bisacodyl and soap suds enemas cause changes in the epithelium of the rectum, and the effect of glycerin on rectal mucosa is unclear. Therefore, these agents should only be used episodically. Mineral oil enemas are used to soften hardened stool in the rectal ampulla.

Other treatment options

More aggressive measures may be necessary for specific types of constipation. These include behavioral therapy and biofeedback for pelvic floor dysfunction, and surgery for slow-transit constipation or Hirschsprung’s disease.

Investigative pharmacologic treatments for constipation include agents that increase colonic contractions (prokinetic drugs) and prostaglandins. These agents have had limited efficacy and troublesome side effects. Therefore, at this time these drugs have limited usefulness in the treatment of constipation.

Fecal impaction

The management of fecal impaction begins with complete evacuation of the colon. Initially, patients with hard stool in the rectum may be given mineral oil retention enemas followed by manual disimpaction. Prior to further treatment, it is important to obtain an abdominal radiograph to rule out mechanical bowel obstruction. If there is no mechanical bowel obstruction, evacuation of the impaction can be accomplished with oral polyethylene glycol (eg, GoLytely) until clear (up to 8 liters or more may be required for complete evacuation).¹⁶ Administration of twice-daily enemas for 3 days or more is an acceptable alternative to oral polyethylene glycol. Lifestyle changes, bulk laxatives, saline, osmotic laxatives, and enemas should be used to maintain regular defecation after the colon has been cleansed. It is reasonable to attempt to withdraw laxatives after several months of regular bowel habits.

Patients with fibromyalgia often resist being referred to a psychiatrist because they fear being told their pain and other somatic symptoms are “all in their heads.” Evidence is mounting that they may be literally correct—the symptoms of fibromyalgia appear to have a physiologic connection with the central nervous system. Abnormal CNS activity, including sleep patterns, response to stress, pain processing, and neurotransmitter levels, has been documented in patients with fibromyalgia.

As psychiatrists, we can reassure these patients—and their primary care physicians and rheumatologists—that we are in a position to help because we:

• have expertise in assessing mood and anxiety disorders and in managing antidepressants, the medication physicians most commonly prescribe for fibromyalgia;
• are skilled in the use of the anticonvulsant gabapentin, which is being used in fibromyalgia for its analgesic and sedative effects;
• can offer much-needed support through psychotherapy, as chronic pain and other fibromyalgia-related symptoms create great stress in these patients’ lives.

Antidepressants are showing promise as an effective treatment for pain, fatigue, and depression in patients with fibromyalgia in studies by our group and others. The following information can help you stay current with the newest understandings of this ailment.

Table 1

CRITERIA FOR DIAGNOSING FIBROMYALGIA

Figure 1 LOCATION OF FIBROMYALGIA TENDER POINTS

To palpate tender point sites, pressure is applied with the thumb pad perpendicularly to each site and the force increased by 1 kg per second until 4 kg of pressure is achieved. Whitening of the thumbnail bed usually occurs when applying the 4-kg force.

Mood disorders in fibromyalgia

A diagnosis of fibromyalgia requires the finding of widespread pain and tenderness at specific anatomic points (Table 1, Figure 1).¹ Most patients also report fatigue, sleep disturbance, and morning stiffness (Box 1).^2-5 American College of Rheumatology criteria do not require exclusionary tests such as radiographs and blood tests for the diagnosis.

Primary care physicians are increasingly making the diagnosis themselves and referring patients to rheumatologists only when conditions other than fibromyalgia are suspected. The differential diagnosis is broad, and other rheumatic and nonrheumatic disorders have similar symptoms, require different treatment, and affect fibromyalgia management (Table 2).⁶

Patients with fibromyalgia often report symptoms of major depressive disorder, such as depressed mood, anxiety, fatigue, and insomnia.⁷ Many psychological studies of such patients have documented increased rates of depressive symptoms.⁸ Depression and anxiety symptoms are common and frequently severe, even among individuals with fibromyalgia in the general population.⁹

Patients’ mood and anxiety disorders correlate highly with the number of medically unexplained symptoms and are associated with functional disability.¹⁰ The presence of psychological symptoms predicts persistent fibromyalgia symptoms,¹¹ and psychological distress is strongly associated with symptom severity.¹²

Evidence for a CNS link

CNS mechanisms appear to contribute to the development of clinical findings in fibromyalgia.

Abnormal sleep A qualitative defect in sleep has been identified in patients with fibromyalgia.¹³ This sleep abnormality consists of inappropriate intrusion of alpha waves (normally seen during wakefulness or REM sleep) into deep sleep (usually characterized by delta waves).¹³ Some researchers believe alpha-delta sleep intrusion is associated with the chronic musculoskeletal pain and fatigue of fibromyalgia and, in turn, is mediated by an abnormality in central serotonergic neurotransmission.¹⁴ This sleep abnormality is not specific to fibromyalgia and can be found in other conditions, however.¹⁵ Debate continues regarding the role of sleep dysregulation in the pathophysiology of fibromyalgia.

Box 1

Stress response Stress appears to precipitate or exacerbate fibromyalgia symptoms in many patients.¹⁶ For example, fibromyalgia appears to be associated with victimization (adult and childhood sexual, physical, and emotional trauma), and this stress may trigger the development of fibromyalgia in some patients.¹⁷

Patients with fibromyalgia appear to develop disturbances in the two major stress-response systems: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system.¹⁶ Although the interpretation of these disturbances is still debated, some researchers suggest that the available data point to reduction in CNS corticotropin releasing hormone (CRH), the key mediator in the HPA axis.^18,19 CRH is also a behaviorally active peptide that leads to physiologic and behavioral arousal when administered centrally to animals.¹⁸ CRH reduction could contribute to the clinical features of fibromyalgia (e.g., fatigue) either directly or indirectly by causing a relative glucocorticoid deficiency.^18,19

Table 2

DIFFERENTIAL DIAGNOSIS OF FIBROMYALGIA

Fibromyalgia is also associated with moderate basal hypocortisolism.^18,19 A relative glucocorticoid deficiency could contribute to fibromyalgia’s characteristic fatigue, arthralgias, myalgias, and disturbances in mood and sleep.¹⁸ This deficiency may also cause some of the immunologic disturbances seen with fibromyalgia.^18,19

Atypical depression, which shares such features of fibromyalgia as profound lethargy, is also associated with inappropriately normal or reduced activation of the HPA axis and a functional deficit in the release of hypothalamic CRH.¹⁸ The unifying feature of HPA axis activity in both atypical depression and fibromyalgia may be a shared hypofunctioning.¹⁸ A more complete understanding of the neuroendocrine changes in fibromyalgia awaits further study.

Pain processing Aberrant CNS processing of pain may also play a role in fibromyalgia.^16,20 Fibromyalgia is sometimes precipitated by physical trauma.²¹ A traumatic injury may start a process in susceptible individuals that leads to an enhanced central processing of painful stimuli characteristic of central sensitization.²² Patients with fibromyalgia often develop an increased response to painful stimuli (hyeralgesia) and experience pain from normally nonnoxious stimuli (allodynia).²⁰

Substance P, an important nociceptive neurotransmitter, may have a role in generating central sensitization.²³ Elevated concentrations of substance P have been found in the cerebrospinal fluid (CSF) of individuals with fibromyalgia.²⁴ Substance P also inhibits CRH release and may contribute to low CRH activity in fibromyalgia.¹⁶

Neurotransmitter defects A functional reduction in serotonergic activity has been demonstrated in patients with fibromyalgia. Schwarz et al²⁵ found a strong negative correlation between serum concentrations of the primary serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and substance P, pain, and insomnia. Evidence also exists of reduced concentrations of the primary norepinephrine metabolite, 3-methoxy-4-hydroxyphenethylene (MHPG), in the CSF of patients with fibromyalgia.²⁶ Reduced serotonin and norepinephrine levels in descending pain-inhibitory pathways may cause the allodynia and hyperalgesia of fibromyalgia.

Pharmacologic treatment

Most studies of pharmacologic treatment of fibromyalgia have examined antidepressants for three reasons:

• There is evidence of the successful use of antidepressants in other chronic pain conditions.²⁷
• These agents are effective for treating mood and anxiety disorders, which frequently occur in patients with fibromyalgia and may share a common physiologic abnormality.²⁸
• Antidepressants might enhance the activity of neurotransmitters such as serotonin and norepinephrine in the descending inhibitory pain pathways, leading to reduced pain perception.²⁹

Tricyclics In randomized, controlled trials, tricyclic medications (including the muscle relaxant cyclobenzaprine) appear to be moderately effective in improving fibromyalgia symptoms. Two meta-analyses of trials of tricyclic medications (amitriptyline, dothiepin, cyclobenzaprine, clomipramine, and maprotiline) have found similar results.^30,31 Our group found the greatest effect on measures of sleep improvement, which may be due in part to tricyclics’ sedative properties.³⁰ Many patients with fibromyalgia, however, cannot tolerate the sedative and other side effects associated with tricyclic agents, even though low dosages (e.g., 25 mg/d of amitriptyline) have typically been used in clinical trials.

SSRIs. Selective serotonin reuptake inhibitors, although likely to be better tolerated than tricyclics, have been examined in only five placebo-controlled trials in fibromyalgia: two with citalopram, and three with fluoxetine. One citalopram study found no significant differences in efficacy between citalopram and a placebo,³² but the other reported significant improvement in one measure of pain and a significant decrease in depressive symptoms compared with the placebo group.³³ No significant differences were found between groups in the global assessment of improvement.

The initial fluoxetine trial in fibromyalgia treatment did not reveal a significant therapeutic effect over a placebo,³⁴ although the study was limited by a high (57%) placebo dropout rate, small sample size (42 subjects), brief duration (3 to 6 weeks after treatment), and restriction of fluoxetine dosage to 20 mg/d. In the two other controlled trials, including one which we recently conducted, fluoxetine was superior to a placebo in reducing pain and other fibromyalgia-associated symptoms.^35,36

In our 12-week investigation (a randomized, placebocontrolled, parallel-group, flexible-dose trial), 60 subjects with fibromyalgia received fluoxetine 20 to 80 mg/d or a placebo.³⁶ Those receiving fluoxetine (mean dosage 45 ±25 mg/d) displayed significantly greater reduction in pain, fatigue, and depression compared with those receiving the placebo. The effect of fluoxetine on pain remained significant after we adjusted for change in depression.

Sertraline was evaluated in an open study of 47 fibromyalgia patients at dosages of 25 to 200 mg/d for 6 weeks. Nearly two-thirds (63%) assessed the efficacy of sertraline as good or very good in the treatment of their symptoms.³⁷ Paroxetine effectively reduced fibromyalgia symptoms in a single-blind study at dosages of 20 mg/d for 3 months.³⁸

SNRIs Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor, has shown promise in the treatment of fibromyalgia in a preliminary open trial conducted by our group.³⁹ Venlafaxine at a mean dosage of 167 mg/d resulted in significant improvement in fibromyalgia symptoms and quality of life compared with baseline. Notably, lifetime comorbid depressive and anxiety disorders were common in this sample, and their presence predicted response of fibromyalgia symptoms to venlafaxine.

Gabapentin Although no studies have been published on fibromyalgia treatment with this anticonvulsant, gabapentin has been found to exert substantial analgesic effects in controlled studies of other kinds of pain, including diabetic neuropathy, post-herpetic neuralgia, and migraines.^40-42 There are also anecdotal reports of its successful use in fibromyalgia.²

Nonpharmacologic treatment

Cardiovascular fitness training, regional sympathetic block, electromyographic biofeedback, hypnotherapy, and electroacupuncture have been reported to have modest efficacy for fibromyalgia symptoms in short-term, randomized controlled trials.^43-46 Other studies, however, have not replicated the efficacy of these treatments.

Cognitive-behavioral therapy has shown promise in preliminary studies.^47,48 Cognitive restructuring techniques that challenge negative thoughts and promote an active, positive, problem-solving approach to pain were found to be important components of fibromyalgia therapy, as were relaxation training, aerobic exercise and stretching, pacing of activities, and family education.⁴⁷

Recommendations

Based on our group’s experience and the limited data available, the following are recommendations for the pharmacologic treatment of fibromyalgia:

• Consider a trial of antidepressant medication for patients with a history of mood (unipolar) or anxiety disorders. First try an SSRI or an SNRI because many patients do not tolerate tricyclics. Use antidepressant therapeutic dosages and an adequate duration of treatment (at least 6 weeks).
• If symptoms do not respond to an adequate trial of first-line medications, treatment with tricyclics appears warranted. Although studies have focused mostly on tertiary amine tricyclics (e.g., amitriptyline), secondary amine agents (e.g., nortriptyline) may be just as effective and better tolerated, allowing for titration to higher dosages.
• Consider combination therapy when needed. For example, in patients who experience relief of pain, fatigue, and depressed mood with fluoxetine but continue to have insomnia, gabapentin can be added at night. Begin with 100 mg/d and increase by 100 mg/d until you see improvement or intolerance. Another option is trazodone, beginning with 50 mg hs. If you add a low-dose tricyclic to an SSRI, be aware of pharmacokinetic interaction and monitor tricyclic levels.
• Gabapentin alone, although it has not been studied in controlled trials of fibromyalgia, may be an option for patients who do not respond to antidepressants. Other pain conditions treated with gabapentin have required dosages of 1,600 to 2,400 mg/d to achieve substantial analgesic effects.

Cardiovascular fitness training is a potentially important component of fibromyalgia treatment. Many patients, however, have difficulty getting started because of increased pain after exercise and disabling fatigue. Treatment with medications as recommended may provide enough relief for patients to start an exercise program. Remind patients to start slowly, increasing the frequency and intensity of exercise as their endurance improves.

Because stress and a history of psychological trauma contribute to the onset and exacerbation of symptoms in some patients, cognitive-behavioral therapy is recommended as an adjunctive treatment as appropriate.

Related resources

• American Fibromyalgia Syndrome Association, Inc. www.afsafund.org
• Arnold LM, et al. Antidepressant treatment of fibromyalgia. A metaanalysis and review. Psychosomatics 2000;41:104-13.
• Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: a drug development perspective. Psychopharmacol Bull 2002;36:165-213.

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyclobenzaprine • Flexeril
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Maprotiline • Ludiomil
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

The author reports that she receives research support from Eli Lilly & Co. and Pfizer Inc. and serves as a consultant and member of the speakers’ bureaus for both of those companies.

Patients with fibromyalgia often resist being referred to a psychiatrist because they fear being told their pain and other somatic symptoms are “all in their heads.” Evidence is mounting that they may be literally correct—the symptoms of fibromyalgia appear to have a physiologic connection with the central nervous system. Abnormal CNS activity, including sleep patterns, response to stress, pain processing, and neurotransmitter levels, has been documented in patients with fibromyalgia.

As psychiatrists, we can reassure these patients—and their primary care physicians and rheumatologists—that we are in a position to help because we:

• have expertise in assessing mood and anxiety disorders and in managing antidepressants, the medication physicians most commonly prescribe for fibromyalgia;
• are skilled in the use of the anticonvulsant gabapentin, which is being used in fibromyalgia for its analgesic and sedative effects;
• can offer much-needed support through psychotherapy, as chronic pain and other fibromyalgia-related symptoms create great stress in these patients’ lives.

Antidepressants are showing promise as an effective treatment for pain, fatigue, and depression in patients with fibromyalgia in studies by our group and others. The following information can help you stay current with the newest understandings of this ailment.

Table 1

CRITERIA FOR DIAGNOSING FIBROMYALGIA

Figure 1 LOCATION OF FIBROMYALGIA TENDER POINTS

To palpate tender point sites, pressure is applied with the thumb pad perpendicularly to each site and the force increased by 1 kg per second until 4 kg of pressure is achieved. Whitening of the thumbnail bed usually occurs when applying the 4-kg force.

Mood disorders in fibromyalgia

A diagnosis of fibromyalgia requires the finding of widespread pain and tenderness at specific anatomic points (Table 1, Figure 1).¹ Most patients also report fatigue, sleep disturbance, and morning stiffness (Box 1).^2-5 American College of Rheumatology criteria do not require exclusionary tests such as radiographs and blood tests for the diagnosis.

Primary care physicians are increasingly making the diagnosis themselves and referring patients to rheumatologists only when conditions other than fibromyalgia are suspected. The differential diagnosis is broad, and other rheumatic and nonrheumatic disorders have similar symptoms, require different treatment, and affect fibromyalgia management (Table 2).⁶

Patients with fibromyalgia often report symptoms of major depressive disorder, such as depressed mood, anxiety, fatigue, and insomnia.⁷ Many psychological studies of such patients have documented increased rates of depressive symptoms.⁸ Depression and anxiety symptoms are common and frequently severe, even among individuals with fibromyalgia in the general population.⁹

Patients’ mood and anxiety disorders correlate highly with the number of medically unexplained symptoms and are associated with functional disability.¹⁰ The presence of psychological symptoms predicts persistent fibromyalgia symptoms,¹¹ and psychological distress is strongly associated with symptom severity.¹²

Evidence for a CNS link

CNS mechanisms appear to contribute to the development of clinical findings in fibromyalgia.

Abnormal sleep A qualitative defect in sleep has been identified in patients with fibromyalgia.¹³ This sleep abnormality consists of inappropriate intrusion of alpha waves (normally seen during wakefulness or REM sleep) into deep sleep (usually characterized by delta waves).¹³ Some researchers believe alpha-delta sleep intrusion is associated with the chronic musculoskeletal pain and fatigue of fibromyalgia and, in turn, is mediated by an abnormality in central serotonergic neurotransmission.¹⁴ This sleep abnormality is not specific to fibromyalgia and can be found in other conditions, however.¹⁵ Debate continues regarding the role of sleep dysregulation in the pathophysiology of fibromyalgia.

Box 1

Stress response Stress appears to precipitate or exacerbate fibromyalgia symptoms in many patients.¹⁶ For example, fibromyalgia appears to be associated with victimization (adult and childhood sexual, physical, and emotional trauma), and this stress may trigger the development of fibromyalgia in some patients.¹⁷

Patients with fibromyalgia appear to develop disturbances in the two major stress-response systems: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system.¹⁶ Although the interpretation of these disturbances is still debated, some researchers suggest that the available data point to reduction in CNS corticotropin releasing hormone (CRH), the key mediator in the HPA axis.^18,19 CRH is also a behaviorally active peptide that leads to physiologic and behavioral arousal when administered centrally to animals.¹⁸ CRH reduction could contribute to the clinical features of fibromyalgia (e.g., fatigue) either directly or indirectly by causing a relative glucocorticoid deficiency.^18,19

Table 2

DIFFERENTIAL DIAGNOSIS OF FIBROMYALGIA

Fibromyalgia is also associated with moderate basal hypocortisolism.^18,19 A relative glucocorticoid deficiency could contribute to fibromyalgia’s characteristic fatigue, arthralgias, myalgias, and disturbances in mood and sleep.¹⁸ This deficiency may also cause some of the immunologic disturbances seen with fibromyalgia.^18,19

Atypical depression, which shares such features of fibromyalgia as profound lethargy, is also associated with inappropriately normal or reduced activation of the HPA axis and a functional deficit in the release of hypothalamic CRH.¹⁸ The unifying feature of HPA axis activity in both atypical depression and fibromyalgia may be a shared hypofunctioning.¹⁸ A more complete understanding of the neuroendocrine changes in fibromyalgia awaits further study.

Pain processing Aberrant CNS processing of pain may also play a role in fibromyalgia.^16,20 Fibromyalgia is sometimes precipitated by physical trauma.²¹ A traumatic injury may start a process in susceptible individuals that leads to an enhanced central processing of painful stimuli characteristic of central sensitization.²² Patients with fibromyalgia often develop an increased response to painful stimuli (hyeralgesia) and experience pain from normally nonnoxious stimuli (allodynia).²⁰

Substance P, an important nociceptive neurotransmitter, may have a role in generating central sensitization.²³ Elevated concentrations of substance P have been found in the cerebrospinal fluid (CSF) of individuals with fibromyalgia.²⁴ Substance P also inhibits CRH release and may contribute to low CRH activity in fibromyalgia.¹⁶

Neurotransmitter defects A functional reduction in serotonergic activity has been demonstrated in patients with fibromyalgia. Schwarz et al²⁵ found a strong negative correlation between serum concentrations of the primary serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and substance P, pain, and insomnia. Evidence also exists of reduced concentrations of the primary norepinephrine metabolite, 3-methoxy-4-hydroxyphenethylene (MHPG), in the CSF of patients with fibromyalgia.²⁶ Reduced serotonin and norepinephrine levels in descending pain-inhibitory pathways may cause the allodynia and hyperalgesia of fibromyalgia.

Pharmacologic treatment

Most studies of pharmacologic treatment of fibromyalgia have examined antidepressants for three reasons:

• There is evidence of the successful use of antidepressants in other chronic pain conditions.²⁷
• These agents are effective for treating mood and anxiety disorders, which frequently occur in patients with fibromyalgia and may share a common physiologic abnormality.²⁸
• Antidepressants might enhance the activity of neurotransmitters such as serotonin and norepinephrine in the descending inhibitory pain pathways, leading to reduced pain perception.²⁹

Tricyclics In randomized, controlled trials, tricyclic medications (including the muscle relaxant cyclobenzaprine) appear to be moderately effective in improving fibromyalgia symptoms. Two meta-analyses of trials of tricyclic medications (amitriptyline, dothiepin, cyclobenzaprine, clomipramine, and maprotiline) have found similar results.^30,31 Our group found the greatest effect on measures of sleep improvement, which may be due in part to tricyclics’ sedative properties.³⁰ Many patients with fibromyalgia, however, cannot tolerate the sedative and other side effects associated with tricyclic agents, even though low dosages (e.g., 25 mg/d of amitriptyline) have typically been used in clinical trials.

SSRIs. Selective serotonin reuptake inhibitors, although likely to be better tolerated than tricyclics, have been examined in only five placebo-controlled trials in fibromyalgia: two with citalopram, and three with fluoxetine. One citalopram study found no significant differences in efficacy between citalopram and a placebo,³² but the other reported significant improvement in one measure of pain and a significant decrease in depressive symptoms compared with the placebo group.³³ No significant differences were found between groups in the global assessment of improvement.

The initial fluoxetine trial in fibromyalgia treatment did not reveal a significant therapeutic effect over a placebo,³⁴ although the study was limited by a high (57%) placebo dropout rate, small sample size (42 subjects), brief duration (3 to 6 weeks after treatment), and restriction of fluoxetine dosage to 20 mg/d. In the two other controlled trials, including one which we recently conducted, fluoxetine was superior to a placebo in reducing pain and other fibromyalgia-associated symptoms.^35,36

In our 12-week investigation (a randomized, placebocontrolled, parallel-group, flexible-dose trial), 60 subjects with fibromyalgia received fluoxetine 20 to 80 mg/d or a placebo.³⁶ Those receiving fluoxetine (mean dosage 45 ±25 mg/d) displayed significantly greater reduction in pain, fatigue, and depression compared with those receiving the placebo. The effect of fluoxetine on pain remained significant after we adjusted for change in depression.

Sertraline was evaluated in an open study of 47 fibromyalgia patients at dosages of 25 to 200 mg/d for 6 weeks. Nearly two-thirds (63%) assessed the efficacy of sertraline as good or very good in the treatment of their symptoms.³⁷ Paroxetine effectively reduced fibromyalgia symptoms in a single-blind study at dosages of 20 mg/d for 3 months.³⁸

SNRIs Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor, has shown promise in the treatment of fibromyalgia in a preliminary open trial conducted by our group.³⁹ Venlafaxine at a mean dosage of 167 mg/d resulted in significant improvement in fibromyalgia symptoms and quality of life compared with baseline. Notably, lifetime comorbid depressive and anxiety disorders were common in this sample, and their presence predicted response of fibromyalgia symptoms to venlafaxine.

Gabapentin Although no studies have been published on fibromyalgia treatment with this anticonvulsant, gabapentin has been found to exert substantial analgesic effects in controlled studies of other kinds of pain, including diabetic neuropathy, post-herpetic neuralgia, and migraines.^40-42 There are also anecdotal reports of its successful use in fibromyalgia.²

Nonpharmacologic treatment

Cardiovascular fitness training, regional sympathetic block, electromyographic biofeedback, hypnotherapy, and electroacupuncture have been reported to have modest efficacy for fibromyalgia symptoms in short-term, randomized controlled trials.^43-46 Other studies, however, have not replicated the efficacy of these treatments.

Cognitive-behavioral therapy has shown promise in preliminary studies.^47,48 Cognitive restructuring techniques that challenge negative thoughts and promote an active, positive, problem-solving approach to pain were found to be important components of fibromyalgia therapy, as were relaxation training, aerobic exercise and stretching, pacing of activities, and family education.⁴⁷

Recommendations

Based on our group’s experience and the limited data available, the following are recommendations for the pharmacologic treatment of fibromyalgia:

• Consider a trial of antidepressant medication for patients with a history of mood (unipolar) or anxiety disorders. First try an SSRI or an SNRI because many patients do not tolerate tricyclics. Use antidepressant therapeutic dosages and an adequate duration of treatment (at least 6 weeks).
• If symptoms do not respond to an adequate trial of first-line medications, treatment with tricyclics appears warranted. Although studies have focused mostly on tertiary amine tricyclics (e.g., amitriptyline), secondary amine agents (e.g., nortriptyline) may be just as effective and better tolerated, allowing for titration to higher dosages.
• Consider combination therapy when needed. For example, in patients who experience relief of pain, fatigue, and depressed mood with fluoxetine but continue to have insomnia, gabapentin can be added at night. Begin with 100 mg/d and increase by 100 mg/d until you see improvement or intolerance. Another option is trazodone, beginning with 50 mg hs. If you add a low-dose tricyclic to an SSRI, be aware of pharmacokinetic interaction and monitor tricyclic levels.
• Gabapentin alone, although it has not been studied in controlled trials of fibromyalgia, may be an option for patients who do not respond to antidepressants. Other pain conditions treated with gabapentin have required dosages of 1,600 to 2,400 mg/d to achieve substantial analgesic effects.

Cardiovascular fitness training is a potentially important component of fibromyalgia treatment. Many patients, however, have difficulty getting started because of increased pain after exercise and disabling fatigue. Treatment with medications as recommended may provide enough relief for patients to start an exercise program. Remind patients to start slowly, increasing the frequency and intensity of exercise as their endurance improves.

Because stress and a history of psychological trauma contribute to the onset and exacerbation of symptoms in some patients, cognitive-behavioral therapy is recommended as an adjunctive treatment as appropriate.

Related resources

• American Fibromyalgia Syndrome Association, Inc. www.afsafund.org
• Arnold LM, et al. Antidepressant treatment of fibromyalgia. A metaanalysis and review. Psychosomatics 2000;41:104-13.
• Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: a drug development perspective. Psychopharmacol Bull 2002;36:165-213.

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyclobenzaprine • Flexeril
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Maprotiline • Ludiomil
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

The author reports that she receives research support from Eli Lilly & Co. and Pfizer Inc. and serves as a consultant and member of the speakers’ bureaus for both of those companies.

Patients with fibromyalgia often resist being referred to a psychiatrist because they fear being told their pain and other somatic symptoms are “all in their heads.” Evidence is mounting that they may be literally correct—the symptoms of fibromyalgia appear to have a physiologic connection with the central nervous system. Abnormal CNS activity, including sleep patterns, response to stress, pain processing, and neurotransmitter levels, has been documented in patients with fibromyalgia.

As psychiatrists, we can reassure these patients—and their primary care physicians and rheumatologists—that we are in a position to help because we:

• have expertise in assessing mood and anxiety disorders and in managing antidepressants, the medication physicians most commonly prescribe for fibromyalgia;
• are skilled in the use of the anticonvulsant gabapentin, which is being used in fibromyalgia for its analgesic and sedative effects;
• can offer much-needed support through psychotherapy, as chronic pain and other fibromyalgia-related symptoms create great stress in these patients’ lives.

Antidepressants are showing promise as an effective treatment for pain, fatigue, and depression in patients with fibromyalgia in studies by our group and others. The following information can help you stay current with the newest understandings of this ailment.

Table 1

CRITERIA FOR DIAGNOSING FIBROMYALGIA

Figure 1 LOCATION OF FIBROMYALGIA TENDER POINTS

To palpate tender point sites, pressure is applied with the thumb pad perpendicularly to each site and the force increased by 1 kg per second until 4 kg of pressure is achieved. Whitening of the thumbnail bed usually occurs when applying the 4-kg force.

Mood disorders in fibromyalgia

A diagnosis of fibromyalgia requires the finding of widespread pain and tenderness at specific anatomic points (Table 1, Figure 1).¹ Most patients also report fatigue, sleep disturbance, and morning stiffness (Box 1).^2-5 American College of Rheumatology criteria do not require exclusionary tests such as radiographs and blood tests for the diagnosis.

Primary care physicians are increasingly making the diagnosis themselves and referring patients to rheumatologists only when conditions other than fibromyalgia are suspected. The differential diagnosis is broad, and other rheumatic and nonrheumatic disorders have similar symptoms, require different treatment, and affect fibromyalgia management (Table 2).⁶

Patients with fibromyalgia often report symptoms of major depressive disorder, such as depressed mood, anxiety, fatigue, and insomnia.⁷ Many psychological studies of such patients have documented increased rates of depressive symptoms.⁸ Depression and anxiety symptoms are common and frequently severe, even among individuals with fibromyalgia in the general population.⁹

Patients’ mood and anxiety disorders correlate highly with the number of medically unexplained symptoms and are associated with functional disability.¹⁰ The presence of psychological symptoms predicts persistent fibromyalgia symptoms,¹¹ and psychological distress is strongly associated with symptom severity.¹²

Evidence for a CNS link

CNS mechanisms appear to contribute to the development of clinical findings in fibromyalgia.

Abnormal sleep A qualitative defect in sleep has been identified in patients with fibromyalgia.¹³ This sleep abnormality consists of inappropriate intrusion of alpha waves (normally seen during wakefulness or REM sleep) into deep sleep (usually characterized by delta waves).¹³ Some researchers believe alpha-delta sleep intrusion is associated with the chronic musculoskeletal pain and fatigue of fibromyalgia and, in turn, is mediated by an abnormality in central serotonergic neurotransmission.¹⁴ This sleep abnormality is not specific to fibromyalgia and can be found in other conditions, however.¹⁵ Debate continues regarding the role of sleep dysregulation in the pathophysiology of fibromyalgia.

Box 1

Stress response Stress appears to precipitate or exacerbate fibromyalgia symptoms in many patients.¹⁶ For example, fibromyalgia appears to be associated with victimization (adult and childhood sexual, physical, and emotional trauma), and this stress may trigger the development of fibromyalgia in some patients.¹⁷

Patients with fibromyalgia appear to develop disturbances in the two major stress-response systems: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system.¹⁶ Although the interpretation of these disturbances is still debated, some researchers suggest that the available data point to reduction in CNS corticotropin releasing hormone (CRH), the key mediator in the HPA axis.^18,19 CRH is also a behaviorally active peptide that leads to physiologic and behavioral arousal when administered centrally to animals.¹⁸ CRH reduction could contribute to the clinical features of fibromyalgia (e.g., fatigue) either directly or indirectly by causing a relative glucocorticoid deficiency.^18,19

Table 2

DIFFERENTIAL DIAGNOSIS OF FIBROMYALGIA

Fibromyalgia is also associated with moderate basal hypocortisolism.^18,19 A relative glucocorticoid deficiency could contribute to fibromyalgia’s characteristic fatigue, arthralgias, myalgias, and disturbances in mood and sleep.¹⁸ This deficiency may also cause some of the immunologic disturbances seen with fibromyalgia.^18,19

Atypical depression, which shares such features of fibromyalgia as profound lethargy, is also associated with inappropriately normal or reduced activation of the HPA axis and a functional deficit in the release of hypothalamic CRH.¹⁸ The unifying feature of HPA axis activity in both atypical depression and fibromyalgia may be a shared hypofunctioning.¹⁸ A more complete understanding of the neuroendocrine changes in fibromyalgia awaits further study.

Pain processing Aberrant CNS processing of pain may also play a role in fibromyalgia.^16,20 Fibromyalgia is sometimes precipitated by physical trauma.²¹ A traumatic injury may start a process in susceptible individuals that leads to an enhanced central processing of painful stimuli characteristic of central sensitization.²² Patients with fibromyalgia often develop an increased response to painful stimuli (hyeralgesia) and experience pain from normally nonnoxious stimuli (allodynia).²⁰

Substance P, an important nociceptive neurotransmitter, may have a role in generating central sensitization.²³ Elevated concentrations of substance P have been found in the cerebrospinal fluid (CSF) of individuals with fibromyalgia.²⁴ Substance P also inhibits CRH release and may contribute to low CRH activity in fibromyalgia.¹⁶

Neurotransmitter defects A functional reduction in serotonergic activity has been demonstrated in patients with fibromyalgia. Schwarz et al²⁵ found a strong negative correlation between serum concentrations of the primary serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and substance P, pain, and insomnia. Evidence also exists of reduced concentrations of the primary norepinephrine metabolite, 3-methoxy-4-hydroxyphenethylene (MHPG), in the CSF of patients with fibromyalgia.²⁶ Reduced serotonin and norepinephrine levels in descending pain-inhibitory pathways may cause the allodynia and hyperalgesia of fibromyalgia.

Pharmacologic treatment

Most studies of pharmacologic treatment of fibromyalgia have examined antidepressants for three reasons:

• There is evidence of the successful use of antidepressants in other chronic pain conditions.²⁷
• These agents are effective for treating mood and anxiety disorders, which frequently occur in patients with fibromyalgia and may share a common physiologic abnormality.²⁸
• Antidepressants might enhance the activity of neurotransmitters such as serotonin and norepinephrine in the descending inhibitory pain pathways, leading to reduced pain perception.²⁹

Tricyclics In randomized, controlled trials, tricyclic medications (including the muscle relaxant cyclobenzaprine) appear to be moderately effective in improving fibromyalgia symptoms. Two meta-analyses of trials of tricyclic medications (amitriptyline, dothiepin, cyclobenzaprine, clomipramine, and maprotiline) have found similar results.^30,31 Our group found the greatest effect on measures of sleep improvement, which may be due in part to tricyclics’ sedative properties.³⁰ Many patients with fibromyalgia, however, cannot tolerate the sedative and other side effects associated with tricyclic agents, even though low dosages (e.g., 25 mg/d of amitriptyline) have typically been used in clinical trials.

SSRIs. Selective serotonin reuptake inhibitors, although likely to be better tolerated than tricyclics, have been examined in only five placebo-controlled trials in fibromyalgia: two with citalopram, and three with fluoxetine. One citalopram study found no significant differences in efficacy between citalopram and a placebo,³² but the other reported significant improvement in one measure of pain and a significant decrease in depressive symptoms compared with the placebo group.³³ No significant differences were found between groups in the global assessment of improvement.

The initial fluoxetine trial in fibromyalgia treatment did not reveal a significant therapeutic effect over a placebo,³⁴ although the study was limited by a high (57%) placebo dropout rate, small sample size (42 subjects), brief duration (3 to 6 weeks after treatment), and restriction of fluoxetine dosage to 20 mg/d. In the two other controlled trials, including one which we recently conducted, fluoxetine was superior to a placebo in reducing pain and other fibromyalgia-associated symptoms.^35,36

In our 12-week investigation (a randomized, placebocontrolled, parallel-group, flexible-dose trial), 60 subjects with fibromyalgia received fluoxetine 20 to 80 mg/d or a placebo.³⁶ Those receiving fluoxetine (mean dosage 45 ±25 mg/d) displayed significantly greater reduction in pain, fatigue, and depression compared with those receiving the placebo. The effect of fluoxetine on pain remained significant after we adjusted for change in depression.

Sertraline was evaluated in an open study of 47 fibromyalgia patients at dosages of 25 to 200 mg/d for 6 weeks. Nearly two-thirds (63%) assessed the efficacy of sertraline as good or very good in the treatment of their symptoms.³⁷ Paroxetine effectively reduced fibromyalgia symptoms in a single-blind study at dosages of 20 mg/d for 3 months.³⁸

SNRIs Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor, has shown promise in the treatment of fibromyalgia in a preliminary open trial conducted by our group.³⁹ Venlafaxine at a mean dosage of 167 mg/d resulted in significant improvement in fibromyalgia symptoms and quality of life compared with baseline. Notably, lifetime comorbid depressive and anxiety disorders were common in this sample, and their presence predicted response of fibromyalgia symptoms to venlafaxine.

Gabapentin Although no studies have been published on fibromyalgia treatment with this anticonvulsant, gabapentin has been found to exert substantial analgesic effects in controlled studies of other kinds of pain, including diabetic neuropathy, post-herpetic neuralgia, and migraines.^40-42 There are also anecdotal reports of its successful use in fibromyalgia.²

Nonpharmacologic treatment

Cardiovascular fitness training, regional sympathetic block, electromyographic biofeedback, hypnotherapy, and electroacupuncture have been reported to have modest efficacy for fibromyalgia symptoms in short-term, randomized controlled trials.^43-46 Other studies, however, have not replicated the efficacy of these treatments.

Cognitive-behavioral therapy has shown promise in preliminary studies.^47,48 Cognitive restructuring techniques that challenge negative thoughts and promote an active, positive, problem-solving approach to pain were found to be important components of fibromyalgia therapy, as were relaxation training, aerobic exercise and stretching, pacing of activities, and family education.⁴⁷

Recommendations

Based on our group’s experience and the limited data available, the following are recommendations for the pharmacologic treatment of fibromyalgia:

• Consider a trial of antidepressant medication for patients with a history of mood (unipolar) or anxiety disorders. First try an SSRI or an SNRI because many patients do not tolerate tricyclics. Use antidepressant therapeutic dosages and an adequate duration of treatment (at least 6 weeks).
• If symptoms do not respond to an adequate trial of first-line medications, treatment with tricyclics appears warranted. Although studies have focused mostly on tertiary amine tricyclics (e.g., amitriptyline), secondary amine agents (e.g., nortriptyline) may be just as effective and better tolerated, allowing for titration to higher dosages.
• Consider combination therapy when needed. For example, in patients who experience relief of pain, fatigue, and depressed mood with fluoxetine but continue to have insomnia, gabapentin can be added at night. Begin with 100 mg/d and increase by 100 mg/d until you see improvement or intolerance. Another option is trazodone, beginning with 50 mg hs. If you add a low-dose tricyclic to an SSRI, be aware of pharmacokinetic interaction and monitor tricyclic levels.
• Gabapentin alone, although it has not been studied in controlled trials of fibromyalgia, may be an option for patients who do not respond to antidepressants. Other pain conditions treated with gabapentin have required dosages of 1,600 to 2,400 mg/d to achieve substantial analgesic effects.

Cardiovascular fitness training is a potentially important component of fibromyalgia treatment. Many patients, however, have difficulty getting started because of increased pain after exercise and disabling fatigue. Treatment with medications as recommended may provide enough relief for patients to start an exercise program. Remind patients to start slowly, increasing the frequency and intensity of exercise as their endurance improves.

Because stress and a history of psychological trauma contribute to the onset and exacerbation of symptoms in some patients, cognitive-behavioral therapy is recommended as an adjunctive treatment as appropriate.

Related resources

• American Fibromyalgia Syndrome Association, Inc. www.afsafund.org
• Arnold LM, et al. Antidepressant treatment of fibromyalgia. A metaanalysis and review. Psychosomatics 2000;41:104-13.
• Kranzler JD, Gendreau JF, Rao SG. The psychopharmacology of fibromyalgia: a drug development perspective. Psychopharmacol Bull 2002;36:165-213.

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyclobenzaprine • Flexeril
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Maprotiline • Ludiomil
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

The author reports that she receives research support from Eli Lilly & Co. and Pfizer Inc. and serves as a consultant and member of the speakers’ bureaus for both of those companies.