Cochrane for Clinicians
Putting Evidence into Practice
Antidepressants for the Treatment of Neuropathic Pain
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This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/reviews/en/ab005454.html.
A collection of Cochrane for Clinicians published in AFP is available online at http://www.aafp.org/afp/cochrane.
Clinical Scenario
A 70-year-old man with a long-standing history of poorly controlled type 2 diabetes presents with increasing burning and tingling in his feet.
Clinical Question
Should antidepressants be used for the treatment of neuropathic pain?
Evidence-Based Answer
Tricyclic antidepressants, particularly amitriptyline, are effective for the treatment of painful diabetic neuropathy and postherpetic neuralgia, and may be beneficial in other neuropathic pain syndromes, but they should be used with caution in patients at increased risk of adverse events.1
Cochrane Abstract
Background. For many years, antidepressant drugs have been used to manage neuropathic pain, and often are the first-choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients.
Objectives. To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. Migraine and headache studies were not considered.
Search Strategy. Randomized trials of antidepressants in neuropathic pain were identified in MEDLINE (1966 to December 2003); EMBASE (1980 to December 2003); the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2004, issue 1; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers and by contacting investigators.
Selection Criteria. Randomized trials reporting the analgesic effects of antidepressant drugs in adult patients with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded.
Data Collection and Analysis. Two reviewers agreed on the included studies, extracted data, and assessed methodologic quality independently. Fifty trials of 19 antidepressants were considered eligible (2,515 patients) for inclusion. Relative risk (RR) estimates and numbers needed to treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects.
Primary Results. Tricyclic antidepressants are effective treatments for neuropathic pain.
Amitriptyline has an NNT of 2 (95% confidence interval [CI], 1.7 to 2.5), RR 4.1 (95% CI, 2.9 to 5.9), for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. There were insufficient data for an assessment of evidence of effectiveness for other antidepressants such as St. John's wort, venlafaxine (Effexor), and l-tryptophan. For diabetic neuropathy, the NNT was 1.3 (95% CI, 1.2 to 1.5), RR 12.4 (95% CI, 5.2 to 29.2 [five studies]); for postherpetic neuralgia, 2.2 (95% CI, 1.7 to 3.1), RR 4.8 (95% CI, 2.5 to 9.5 [three studies]). There was evidence that tricyclic antidepressants are not effective in human immunodeficiency virus-related neuropathies.
The number needed to harm (NNH) for major adverse effects, defined as an event leading to withdrawal from a study, was 16 (95% CI, 10 to 45). The NNH for minor adverse effects was 4.6 (95% CI, 3.3 to 6.7).
Reviewers' Conclusions. Antidepressants are effective for a variety of neuropathic pains. The best evidence available is for amitriptyline. There are only limited data for the effectiveness of SSRIs. It is not possible to identify the most effective antidepressant until more studies of SSRIs are conducted.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Practice Pointers
Neuropathic pain typically is a burning or "shock-like" pain caused by damage to the peripheral or central nervous system or both. It can be constant or can occur intermittently with paroxysmal attacks, and also may be associated with significant hypersensitivity. Painful diabetic neuropathy affects up to 3 million Americans, and postherpetic neuralgia affects another 1 million.2 Other causes of neuropathic pain include trigeminal neuralgia, central neuropathic pain, and human immunodeficiency virus (HIV) neuropathy. Treatment can be difficult, because neuropathic pain often responds poorly to nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates, but antidepressants3 and the anticonvulsants gabapentin (Neurontin) and carbamazepine (Tegretol) have shown promise.4-6
This Cochrane review1 found that the majority of studies of antidepressants for neuropathic pain focused on tricyclic antidepressants, most commonly amitriptyline. When the tricyclic antidepressants amitriptyline and desipramine (Norpramin) were compared with placebo, one of every two patients treated experienced at least moderate relief of neuropathic pain (number needed to treat = 2). However, multiple studies comparing tricyclic antidepressants found no evidence that one was superior to another. No high-quality evidence comparing tricyclic antidepressants with anticonvulsants was found.
The Cochrane review also evaluated studies with respect to specific causes of neuropathic pain. There was good evidence for the effect of tricyclic antidepressants for diabetic neuropathy, but only limited evidence of effectiveness was available regarding the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac), citalopram (Celexa), and paroxetine (Paxil). There also was evidence that tricyclic antidepressants are effective for postherpetic neuralgia. There was some evidence of benefit from tricyclic antidepressants for central neuropathic pain, but tricyclic antidepressants were not effective in HIV neuropathy.
Treatment recommendations from the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain, published in the Archives of Neurology, advocate five options for the initial treatment of neuropathic pain: tricyclic antidepressants, gabapentin, 5% lidocaine patch (Lidoderm), opioids, and tramadol (Ultram).2 This conference was sponsored by the manufacturer of the 5% lidocaine patch. The recommendations cite evidence supporting the use of gabapentin for postherpetic neuralgia, diabetic neuropathy, and mixed neuropathic pain syndromes; the lidocaine patch for postherpetic neuralgia; opioids for postherpetic neuralgia and diabetic neuropathy; and tramadol for diabetic neuropathy and painful polyneuropathy. They also note that although tricyclic antidepressants were the first medications to be demonstrated effective for neuropathic pain in placebo-controlled trials, they must be used cautiously because of the potential for adverse effects.2
The best evidence on antidepressants for neuropathic pain supports the use of tricyclic antidepressants for painful diabetic neuropathy and postherpetic neuralgia. Tricyclic antidepressants should be used with caution in older persons because of the potential for adverse effects including drowsiness, dry mouth, blurred vision, constipation, and urinary retention,1 and caution also is required in patients with underlying cardiovascular disease, glaucoma, or autonomic neuropathy.2 Although anticonvulsants also have been demonstrated effective for neuropathic pain, there is no good evidence comparing the relative safety and effectiveness of tricyclic antidepressants with anticonvulsants or other agents for neuropathic pain. Selection of an agent for treating neuropathic pain should be guided by the underlying diagnosis, an awareness of any comorbid conditions or risk factors, and patient preference.
The Author
William E. Cayley, Jr., M.D., M.Div., is assistant professor at the University of Wisconsin Eau Claire Family Medicine Residency Program, Eau Claire, and practices at the Sacred Heart and Luther hospitals in Eau Claire.
Address correspondence to William E. Cayley, Jr., M.D., M.Div., Augusta Family Medicine Clinic, Eau Claire Family Medicine Residency, University of Wisconsin, Department of Family Medicine, 617 West Clairemont, Eau Claire, WI 54701 (e-mail: bcayley@yahoo.com). Reprints are not available from the author.
REFERENCES
1. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2005;(3):CD005454.
2. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-34.
3. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005;96:399-409.
4. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005;(3):CD005452.
5. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database Syst Rev 2005;(3):CD005451.
6. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev 2005;(3):CD001133.
Cochrane Briefs
Pharmacologic Treatment of Psychotic Depression
Clinical Question
What is the best treatment for depression with psychotic features?
Evidence-Based Answer
An antidepressant such as imipramine (Tofranil) or sertraline (Zoloft), possibly with the addition of an antipsychotic, is the preferred initial pharmacologic treatment for psychotic depression.
Practice Pointers
About 15 percent of patients with major depression exhibit psychotic features such as hallucinations or delusions. Electroconvulsive therapy often is used to treat psychotic depression and has been shown to be effective in comparisons with sham electroconvulsive therapy. Typically, however, it is not considered first-line therapy, and it has not been compared with pharmacologic treatment in a randomized controlled trial (RCT). Most patients initially are treated pharmacologically, and this review by Wijkstra and colleagues compared an antidepressant alone, an antipsychotic alone, and the combination of both.
Only 10 RCTs with a total of 548 patients were identified after a thorough search of the literature. Although only double-blinded studies with appropriate randomization and intention-to-treat analysis were included, most studies were small (mean of 55 patients), and differing dosages and treatment protocols made it inappropriate to combine results from different studies. The conclusions that could be drawn from this literature, therefore, are limited.
The authors found that an antidepressant alone was effective (four RCTs; relative risk [RR] 2.06; 95% confidence interval [CI], 1.41 to 3.00), but an antipsychotic alone was not. Four studies compared different antidepressants and found that imipramine was more effective than mirtazapine (Remeron) and fluvoxamine (Luvox), that sertraline was more effective than paroxetine (Paxil), and that there was no difference between fluvoxamine and venlafaxine (Effexor). Based on these limited data, the preferred initial agents are imipramine and sertraline. There was a nonsignificant trend toward greater effectiveness of the combination of antidepressant and antipsychotic over an antidepressant alone (two studies, RR 1.44; 95% CI, 0.86 to 2.41). An important practice point for these patients that was not addressed by this meta-analysis is that they should be strongly considered for hospitalization.1
Source: Wijkstra J, et al. Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev 2005;(4):CD004044.
REFERENCES
1. Institute for Clinical Systems Improvement. Major depression in adults for mental health care. Bloomington, Minn.: Institute for Clinical Systems Improvement, 2004.
Long-Acting Beta2 Agonists as Steroid-Sparing Agents
Clinical Question
For patients with asthma, does the addition of a long-acting beta2 agonist allow the dosage of maintenance inhaled corticosteroids to be reduced while maintaining asthma control?
Evidence-Based Answer
For adult patients who are taking a minimum maintenance dosage of inhaled corticosteroid for asthma, adding a long-acting beta2 agonist permits reduction of the dosage of inhaled corticosteroid by 253 mcg beclomethasone equivalent per day without worsening the patient's symptoms. In patients taking higher dosages of corticosteroids, the effect of adding a long-acting beta2 agonist was even more pronounced, with a mean reduction in their maintenance inhaled corticosteroid of 600 mcg beclomethasone equivalent per day. There is no evidence of improved symptoms with combination treatment, and it is not recommended as initial treatment for asthma.
Practice Pointers
In adults and children whose asthma is not adequately controlled with inhaled corticosteroids, adding a long-acting beta2 agonist improves lung function and reduces the risk of exacerbation. Adding a long-acting beta2 agonist does not increase serious side effects or withdrawal rates when compared with inhaled steroids alone.1 Long-acting beta2 agonists alone have proven effective compared with placebo, but there are serious concerns about safety. A large study comparing salmeterol (Serevent) with placebo was stopped prematurely because of an increase in the risk of death in the active treatment group.2-4
Gibson and colleagues studied long-acting beta2 agonists as corticosteroid-sparing agents to further refine their role in the treatment of asthma. They found 10 parallel randomized controlled trials involving adult patients who required daily inhaled corticosteroids. Trial quality was good, and the power of the studies was adequate. The trials compared inhaled corticosteroids with combination treatment with reduced-dosage inhaled corticosteroids and a long-acting beta2 agonist. Patients were followed for three to 12 months. The mean reduction in the dosage of inhaled corticosteroid was 60 percent.
The researchers found no significant differences between the groups in exacerbations requiring oral steroids or in withdrawal from the study because of worsening airway inflammation. In the group that used combined treatment, forced expiratory volume in one second improved compared with baseline (weighted mean difference 0.10; 95% confidence interval, 0.07 to 0.12), there was a small but significant improvement in morning peak expiratory flow, and there were fewer days when short-acting beta2 agonists were needed. These results suggest that the beta2 agonists were not masking worsening airway inflammation.
Because adding a long-acting beta2 agonist is effective in reducing the steroid dosage in patients maintaining disease control with long-term inhaled steroids, it is reasonable to question whether combined treatment should be the initial treatment in patients with mild to moderate airway obstruction. This question was addressed by Ni Chroinin and colleagues,5 who found that in a steroid-naive population with asthma, combined therapy does not significantly reduce the rate of exacerbations over inhaled corticosteroids alone. Combined thereapy may improve lung function and symptom-free days, but it does not reduce the use of short-acting beta2 agonists. Overall, there is not sufficient evidence to recommend initiating combined therapy for patients who have never had a trial of inhaled corticosteroids, particularly given the cost of two drugs compared with one.5
Source: Gibson PG, et al. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev 2005;(4):CD005076.
REFERENCES
1. Ni Chroinin M, Greenstone IR, Danish A, Magdolinos H, Masse V, Zhang X, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev 2005;(4):CD005535.
2. Walters EH, Walters JA, Gibson MD. Long-acting beta2-agonists for stable chronic asthma. Cochrane Database Syst Rev 2003;(3):CD001385.
3. Lemanske RF Jr, Sorkness CA, Mauger EA, Lazarus SC, Boushey HA, Fahy JV, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001;285:2594-603.
4. Lurie P, Wolfe SM. Misleading data analyses in salmeterol (SMART) study [Letter]. Rickard KA. GlaxoSmithKline's reply. Lancet 2005;366:1261-2.
5. Ni Chroinin M, Greenstone IR, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults. Cochrane Database Syst Rev 2004;(4):CD005307.
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