See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/14027493 The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain Article in Journal of General Internal Medicine · July 1997 DOI: 10.1007/s11606-006-5088-3 · Source: PubMed CITATIONS READS 130 26 3 authors, including: Thomas O Staiger University of Washington Seattle 22 PUBLICATIONS 1,046 CITATIONS SEE PROFILE All content following this page was uploaded by Thomas O Staiger on 12 December 2016. The user has requested enhancement of the downloaded file. The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain Alan C. Jung, MD, Thomas Staiger, MD, Mark Sullivan, MD, PhD OBJECTIVE: To assess the effectiveness of selective seroto- Fluoxetine was introduced as the first selective sero- nin reuptake inhibitors (SSRIs) in the management of chronic tonin reuptake inhibitor (SSRI) in the United States in pain. 1988. Since then, SSRIs have become the most frequently METHODS: Randomized, controlled trials of SSRIs in the prescribed antidepressant medications owing to their fa- management of chronic pain were identified by searching vorable side-effect profile.4 More than half of antidepres- MEDLINE from 1966 to 1997 and by contacting the manufac- sant prescriptions written in the primary care setting are turers of SSRIs available in the United States. for conditions other than depression.5 There is consider- MAIN RESULTS: Nineteen studies were identified, including able interest in the use of SSRIs for the management of 10 on the treatment of headache, 3 on diabetic neuropathy, 3 chronic pain, although they are not currently approved by on fibromyalgia, and 3 on mixed-chronic pain. SSRIs were the Food and Drug Administration for this purpose. This consistently helpful for mixed-chronic pain. Results were review summarizes available data on the value of these conflicting for migraine headache, tension headache, dia- medications for pain control in several clinical situations. betic neuropathy, and fibromyalgia. CONCLUSIONS: SSRIs appear to be beneficial for mixed- METHODS chronic pain. It is unclear, from the available evidence, whether SSRIs are beneficial for migraine headaches, tension head- We used the National Library of Medicine search en- aches, diabetic neuropathy, or fibromyalgia. For those pa- gine to search MEDLINE from 1966 to 1997 using the tients it may be reasonable to reserve SSRIs for those who medical subject heading (MeSH) term “pain,” exploding it, fail to respond to other medications or who are intolerant of and adding the following words in all fields: pain, neurop- their side effects. athy, migraine, and fibromyalgia. We also searched using KEY WORDS: chronic pain, management of; selective seroto- the MeSH term “serotonin uptake inhibitors” and the fol- nin reuptake inhibitors. lowing words in all fields: sertraline, paroxetine, fluoxe- J GEN INTERN MED 1997;12:384–389. tine, fluvoxamine, femoxetine, zimelidine, and citalopram. We combined results of these two searches with the term “and,” and selected for review randomized double-blind, he clinical management of chronic pain remains a controlled studies published in English and performed on Tchallenge. Despite advances in pain research and humans. References from studies reviewed provided addi- clinical treatment, rates of disability due to chronic pain tional sources of information. We also requested relevant continue to climb worldwide.1 Although chronic pain is studies from the manufacturers of Prozac (fluoxetine), treated with many medications, such as tricyclic anti- Zoloft (sertraline), Luvox (fluvoxamine), and Paxil (parox- depressants, nonsteroidal anti-inflammatory drugs, anti- etine), the four SSRIs available in the United States. convulsants, and opioids, none has shown outstanding ef- ficacy. Narcotics are usually avoided because of the risk HEADACHE of developing tolerance, dependence, and functional dete- rioration.2 Tricyclic antidepressants have proven efficacy Ten studies evaluated the efficacy of SSRIs in the treat- in the treatment of chronic pain conditions such as dia- ment of chronic headache (Table 1). Saper et al. compared betic neuropathy, fibromyalgia, chronic headaches, and fluoxetine (20–40 mg/d) with placebo in a randomized, post-herpetic neuralgia.3 Their ability to relieve pain in double-blind study of 64 patients with chronic daily head- these conditions appears to be independent of their anti- ache (headache more than 16 d/mo) and 58 patients with depressant effect and may be related to their effect on migraine headache (4–12 attacks/mo).6 After 3 months, neuronal reuptake of serotonin and norepinephrine. Un- patients with chronic daily headache taking fluoxetine fortunately, side effects including dry mouth, constipa- showed a 53% mean improvement in self-rated, overall tion, orthostatic hypotension, and urinary retention often headache status compared with a 17% mean improvement limit their use. in those receiving placebo (p 5 .029). Of those patients with chronic daily headache taking fluoxetine, 47% also ex- perienced at least a 50% improvement in mood compared with 24% of those in the placebo group (p 5 .097). Pa- Received from the Department of Medicine (ACJ, TS) and the tients receiving fluoxetine had a modest decrease in head- Department of Psychiatry, Multidisciplinary Pain Center (MS), University of Washington, Seattle. ache frequency but not severity. In contrast to its effect Address correspondence and reprint requests to Dr. Jung: on chronic daily headache, fluoxetine was not effective on Department of Medicine Residency Office, P.O. Box 356421, any measure of migraine headache with the exception of a University of Washington, Seattle, WA 98195. modest mood improvement at the end of the third month. 384 JGIM Volume 12, June 1997 385 Table 1. Randomized, Double-Blind, Controlled Studies of SSRIs in Headache Headache Study Design Type N Results Saper et al.,6 1994 Fluoxetine vs Chronic daily 64 Mean improvement in treated 53% vs 17% with placebo placebo (p 5 .029). Migraine 58 Fluoxetine 5 placebo Langemark and Olesen,7 Paroxetine vs sulpiride, Chronic 50 Both groups improved (p , .05) in headache 1994 crossover for tension score and analgesic use compared to baseline. nonresponders Patients testing both drugs showed better relief from sulpiride (p 5 .03). Manna et al.,8 1994 Fluvoxamine vs Chronic 40 Both groups improved from baseline in headache mianserine tension frequency (p , .01), pain severity (p , .01), and analgesic consumption (p , .05). Bendtsen et al.,9 1996 Threeway crossover Chronic 40 Amitriptyline reduced the area under the headache of amitriptyline vs tension curve compared to placebo (p 5 .002). Citalopram 5 citalopram vs placebo placebo (p 5 .68). Andersson and Petersen,10 Femoxetine vs Migraine 49 Both groups had fewer migraine attacks and fewer 1981 propranolol headache days compared to baseline (p , .001). There was no difference between treatment groups. Zeeberg et al.,11 1981 Femoxetine vs Migraine 59 Femoxetine 5 placebo placebo Orholm et al.,12 1986 Femoxetine vs Migraine 65 Femoxetine 5 placebo placebo Kangsmaniemi et al.,13 Crossover of Migraine 29 Compared to baseline, those receiving propranolol 1983 femoxetine vs had a decrease in attack frequency, headache propranolol index, and use of attack relieving drugs (p , .05). Femoxetine showed no significant effect. Adly et al.,14 1992 Fluoxetine vs Migraine 32 Headache scores in the fluoxetine treated group placebo improved compared to placebo group (p , .05); 14 patients failed to complete study. Bánk,15 1994 Fluvoxamine vs Migraine 64 Both groups improved over baseline (p , .02). amitrityline Langemark and Olesen compared paroxetine (20–30 for 8 weeks. Treatment periods were separated by 2-week mg/d) with sulpiride (200–400 mg/d), a dopamine antag- washout periods. Amitriptyline reduced the area under onist used as a neuroleptic in Europe, in a randomized, the headache curve (the sum of the daily recordings of double-blind, crossover study of 50 nondepressed pa- headache duration 3 headache intensity) by 30% com- tients with chronic tension-type headache.7 Both treat- pared with placebo (p 5 .002), but citalopram had no sig- ment groups experienced a significant decrease in head- nificant effect (p 5 .68). ache scores and analgesic use over 8 weeks compared Andersson and Petersen compared femoxetine (400 with baseline (p , .05). Patients testing both drugs showed mg/d), an SSRI not available in the United States, with significantly better relief from sulpiride (p 5 .03). A pla- propranolol (160 mg/d) for the prophylaxis of migraine cebo arm was not included in the study. headache.10 They randomized 49 patients in a double- Manna and colleagues enrolled 40 patients in a ran- blind, crossover trial of 6 months’ duration. There was no domized, double-blind comparison of fluvoxamine (50– significant difference between propranolol and femoxetine 100 mg/d) and mianserine (30–60 mg/d), a presynaptic, in the number of headache days or the number of mi- serotonin receptor antagonist, for the treatment of chronic, graine attacks. There was, however, significant improve- tension-type headache.8 Both treatment groups showed ment in headache parameters with each drug when com- significant improvement in headache frequency (p , .01), pared with baseline (p , .001). pain severity (p , .01), and analgesic use (p , .05). Flu- Zeeberg et al. studied the prophylactic effect on mi-