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Antidepressants for diabetic neuropathy and postherpetic neuralgia

Clinical bottom line

Antidepressants are effective treatments for diabetic neuropathy (NNT 3.4, 95% confidence interval 2.6 to 4.7) and postherpetic neuralgia (NNT 2.1, 1.7 to 3.0) compared with placebo. The NNH for any patient to have a minor adverse effect with antidepressant was 2.7 (2.1 to 3.9) and for a major adverse effect was 17 (10-43).


For over thirty years the management of neuropathic pain has involved the use of both antidepressants and anticonvulsants, but which drug class should be first line choice remains unclear. The dogma that the character of the pain was predictive of the response, burning pain responding to antidepressants and shooting pain to anticonvulsants, was shown to be incorrect in diabetic neuropathy, where patients experiencing both burning and shooting pain responded to tricyclic antidepressants. Most studies on neuropathic pain have involved diabetic neuropathy and postherpetic neuralgia, because these conditions represent the majority of patients with neuropathic pain.

SYSTEMATIC REVIEW

SL Collins et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. Journal of Pain and Symptom Management 2000 20: 449-458.

Searching involved numerous electronic databases including MEDLINE, EMBASE, CINAHL, Sigle, PubMed and the Cochrane Library, plus in-house databases of randomised controlled trials in pain. The inclusion criteria used were: full journal publication, adult patients, double-blind design, random allocation to treatment groups which included placebo and either an antidepressant or an anticonvulsant for the treatment of chronic pain due to diabetic neuropathy or postherpetic neuralgia. An adequate description of the original authors’ method of clinical diagnosis was required to ensure an accurate diagnosis of the two conditions. For postherpetic neuralgia the pain must have been present for more than three months after zoster eruption to limit the chance of spontaneous cessation of symptoms.

A clinically relevant outcome was defined as a measure equivalent to at least 50% pain relief after the longest reported duration of treatment. This was extracted as dichotomous information from the following hierarchy of outcome measures:

The majority of studies used a cross-over design and results are presented in terms of patient episodes rather than actual numbers of patients. One patient episode represents the result for one patient completing one part of the cross-over. So for a trial where the patient was crossed-over from placebo to active this would generate two patient episodes.

Adverse effects were classified as minor if reported by a patient who then continued to take the medication and completed the trial. A major adverse effect was one causing the patient to withdraw from the study. Withdrawal due to lack of efficacy was not counted as an adverse effect.

Findings

The studies of antidepressants in diabetic neuropathy and postherpetic neuralgia were small, ranging from 12 to 92 patient episodes in total. Consequently the results of individual trials varied greatly, both in diabetic neuropathy (Figure 1) and postherpetic neuralgia (Figure 2).

Figure 1: Trials of antidepressants versus placebo in diabetic neuropathy

Figure 2: Trials of antidepressants versus placebo in postherpetic neuralgia

Pooled results are shown in Table 1. Over both conditions, 64% of patients had an outcome equivalent to more than 50% pain relief with antidepressant, compared with 30% with placebo. The NNT for at least 50% pain relief compared with placebo was 2.9 (2.4 to 3.7). For every patient who received benefit, one also had a minor adverse effect that did not lead to discontinuation. Nearly 1 patient in 12 discontinued treatment because adverse effects were intolerable, with a NNH of 17 (10-43).

Table 1: Summary results of efficacy and harm for antidepressants in diabetic neuropathy and postherpetic neuralgia

Number of patients improved or harmed number/total (%)
Trials Patient episodes Antidepressant Placebo Relative benefit (95% CI) NNT
(95% CI)
Efficacy
Diabetic neuropathy 16 491 185/281 (66%) 76/210 (36%) 1.7 (1.4 - 1.9) 3.4 (2.6 - 4.7)
Postherpetic neuralgia 3 145 44/77 (57%) 7/68 (10%) 5.5 (2.7 - 11) 2.1 (1.7 - 3.0)
Both conditions 19 636 229/358 (64%) 83/278 (30%) 1.9 (1.6 - 2.3) 2.9 (2.4 - 3.7)
Harm NNH
(95% CI)
Minor adverse effect 7 281 114/163 (70%) 39/118 (33%) 2.3 (1.8 - 2.9) 2.7 (2.1 - 3.9)
Major adverse effect 16 536 27/325 (8%) 5/211 (1%) 2.6 (1.4 - 5) 17 (10 - 43)

Comment

This review updated previous reviews and confirmed that antidepressants are effective in patients with diabetic neuropathy and postherpetic neuralgia. The degree of benefit, an outcome equivalent to at least 50% pain relief, was valuable, and with an NNT of 3, efficacy was equivalent to that seen in effective analgesics in acute pain (10 mg intramuscular morphine, for instance). Two thirds of patients given antidepressants benefited. For every patient who benefited, one had a minor adverse effect, but continued with the treatment. There were few differences in the efficacy and harm seen with antidepressants and anticonvulsants.

Other reviews on neuropathic pain

It is an interesting observation that rather a lot of reviews (most systematic) have been done around neuropathic pain. It is impossible to abstract them all, and probably unrewarding, in that they cover virtually the same papers. For those readers with a particular interest, a list of those we have found is given below.

  1. BS Alperand and PR Lewis. Treatment of postherpetic neuralgia. A systematic review of the literature. Journal of Family Practice 2002 51:121-8.
  2. LM Arnold et al. Antidepressant treatment of fibromyalgia. Psychsomatics 2000 41:104-13.
  3. R Browning et al. Cyclobenzaprine and back pain: a meta-analysis. Archives of Internal Medicine 2001 161:1613-20.
  4. SL Collins et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. Journal of Pain and Symptom Management 2000 20:449-58.
  5. MR Denkers et al. Dorsal root entry zone lesioning used to treat central neuropathic pain in patients with traumatic spinal cord injury: a systematic review. Spine 2002 27:E177-84.
  6. DA Fishbain et al. Do antidepressants have an analgesic effect in psychogenic pain and somatoform pain disorder? A meta-analysis. Psychosomatic Medicine 1998 60:503-9.
  7. AD Furlanand et al. Chemical sympathectomy for neuropathic pain: does it work? Case report and systematic literature review. Clinical Journal of Pain 2001 17:327-36.
  8. TS Jensen et al. The clinical picture of neuropathic pain. European Journal of Pharmacology 2001 429:1-11.
  9. AC Jung et al. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. Journal of General Internal Medicine 1997 12:384-390.
  10. N Katz. Neuropathic pain in cancer and AIDS. Clinical Journal of Pain 2000 16:S41-8.
  11. M Koltzenburg. Painful neuropathies. Current Opinion in Neurology 1998 11:515-21.
  12. S Ladhaniand, HC Williams. The management of established postherpetic neuralgia: a comparison of the quality and content of traditional vs. systematic reviews. British Journal of Dermatology 1998 139: 66-72.
  13. T Lancaster et al. Primary care management of acute herpes zoster: systematic review of evidence from randomized controlled trials. British Journal of General Practice 1995 45:39-45.
  14. ME Lynch. Antidepressants as analgesics: a review of randomized controlled trials. Psychopharmacology of Pain 2001 26:30-6.
  15. LA Martinand, NA Hagen. Neuropathic pain in cancer patients: mechanisms syndromes, and clinical controversies. Journal of Pain and Symptom Management 1997 14:99-117.
  16. TJ Martinand, JC Eisenach. Pharmacology of opioid and nonopioid analgesics in chronic pain states. Journal of Pharmacology and Experimental Therapeutics 2001 299:811-7.
  17. H McQuay et al. Anticonvulsant drugs for management of pain: a systematic review. Br Med J 1995 311:1047-52.
  18. HJ McQuay. Systematic review of outpatient services for chronic pain control. Health Technology Assessment 1997;1.
  19. HJ McQuay et al. A systematic review of antidepressants in neuropathic pain. Pain 1996 68:217-27.
  20. MA Mellegers et al. Gabapentin for neuropathic pain: systematic review of controlled and uncontrolled literature. Clinical Journal of Pain 2001 17:284-95.
  21. A Nicolucci et al. A meta-analysis of trials on aldose reductase inhibitors in diabetic peripheral neuropathy. Diabetic Medicine 1996 13:1017-26.
  22. A Nicolucci et al. The efficacy of tolrestat in the treatment of diabetical peripheral neuropathy. A meta-analysis of individual patient data. Diabetes Care 1996 19:1091-6.
  23. PG O'Malley et al. Treatment of fibromyalgia with antidepressants: a meta-analysis. Journal of General Internal Medicine 2000 15:659-66.
  24. PG O'Malley et al. Antidepressant therapy for unexplained symptoms and symptom syndromes. Journal of Family Practice 1999 48:980-9.
  25. P Onghenaand, B Van Houdenhove. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 1992 49:205-19.
  26. M Padilla et al. Topical medications for orofacial neuropathic pain: a review. Journal of the American Dental Association 2000 131:184-95.
  27. SM Salerno et al. The effect of antidepressant treatment on chronic back pain. Archives of Internal Medicine 2002 162:19-24.
  28. GE Tomkins et al. Treatment of chronic headache with antidepressants: a meta-analysis. American Journal of Medicine 2001 111:54-63.
  29. J Volmink et al. Treatments for postherpetic neuralgia: A systematic review of randomized controlled trials. Family Practice 1996 13:84-91.