Antidepressant Analgesics

SUMMARY

This chapter provides information on the pharmacology, guidelines, recent individual quality randomized controlled trials (RCTs), and data regarding efficacy and safety from recent systematic reviews involving antidepressants and pain. Of particular interest in these studies are the clinical meaningfulness of the results and how the drugs compare with the standard treatment of the more specific subclass of tricyclic antidepressants and other analgesics. An important concern is the limited external validity or generalizability of trial data on neuropathic pain to the same disorders in ordinary practice. The presence of negative RCTs of antidepressants for other painful states may suggest that the trial results are limited in this regard as well. The importance of comparative effectiveness research is raised. Head-to-head RCTs comparing different antidepressants and other analgesics for neuropathic pain are reviewed, and in their absence the value of indirect comparative measures such as the number needed to treat and to harm are discussed. Despite the increase in placebo-controlled RCTs of antidepressants for painful conditions, no striking advance or “magic bullet” for monotherapy has appeared. There continues to be a need for comparative effectiveness research on new antidepressants by quality RCTs that compare new and old drugs directly to guide clinical decision making. Because of deficiencies in this area and evidence of poor generalizability, combinations of the useful antidepressants with other analgesic drugs need to be considered.

Introduction

Antidepressants are one of the oldest pharmacological treatments of chronic pain and have been subjected to many randomized controlled trials (RCTs). This chapter reviews the pharmacological aspects of these drugs and the evidence-based data regarding efficacy and safety in patients with acute pain, cancer pain, and chronic non-cancer pain (arthritis, fibromyalgia [FM], headache, low back pain [LBP], miscellaneous chronic pain, and neuropathic pain [NP]) [ Table 34-1 ]). We consider the tricyclic antidepressants (TCAs), heterocyclics, selective serotonin reuptake inhibitors (SSRIs), combined serotonin–noradrenalin reuptake inhibitors (SNRIs), and the monamine oxidase (MAO) inhibitor moclobemide ( Table 34-2 ). In the 2006 edition of this book we provided evidence of an analgesic action of some of the antidepressants supported by RCTs and the relief of different components of particularly NP conditions, namely, steady pain, jabbing, and evoked pain (allodynia). We noted that other analgesics could now be regarded as first-line therapy (the gabapentinoids) but that there was no good evidence for abandoning TCAs as an initial choice. Furthermore, evidence was provided for the lesser utility of more selective serotonergic (S) and noradrenergic (N) agents. Comparative data were predominantly based on the number needed to treat (NNT) ( Table 34-3 ) and to harm (NNH). We suggested that there was a need for combination therapy with drugs such as anticonvulsants and opioids in some patients. We commented that further comparative studies were necessary and more effective treatments were needed. In this edition we review evidence-based guidelines from different countries (Canada, United States, and Europe) that have reasonable concordance, systematic reviews of antidepressants for different pain conditions, and also individual quality RCTs of TCAs, SSRIs, and SNRIs such as duloxetine, venlafaxine, and milnacipran. We address the issue of the limited comparative effectiveness research on antidepressants, particularly for NP, in the form of head-to-head trials and review these data and indirect comparative figures (NNT, NNH). We address the important issues of clinical meaningfulness in individual trials, the external validity (generalizability to ordinary practice) of these drugs, and the limited efficacy of drugs, which leads to the need for combinations of antidepressants with anticonvulsants and opioids in many patients. Finally, we provide practical guidelines for the use of antidepressants in the management of chronic pain.

Table 34-1

Antidepressants in Pain: 110 Randomized Controlled Trials

SOURCE AND CONDITION	AGENT, DOSE, AND DURATION OF STUDY	NO. ENTERED/NO. COMPLETED	EFFECT YES/NO	JADAD SCALE MAX = 5	COMMENTS
Acute Pain
Dental pain	Desipramine, 75 mg Amitriptyline, 75 mg Placebo 1 wk	15/group	No No	3	Parallel design TCAs given 1 wk preop, morphine one dose postop; no change in postop pain Increased analgesia with desipramine only if morphine given
Pain after major surgery	Desipramine, 50 mg or Placebo on day 1 postop	62/88	No enhancement of high- or low-dose morphine analgesia	3	Parallel design
Total hip/knee arthroplasty	Amitriptyline, 50 mg Placebo 3 days	14/28 14/28	No No	4	Parallel design Amitriptyline, 50 mg, or placebo solution 3 days postop
Impacted 3rd molar extraction	Desipramine, 50 mg qhs × 7 days preop, or desipramine, 50 mg/day × 3 days preop, or desipramine, 50 mg/day × 3 days starting 7 days preop, or placebo	60/60	Desipramine given early in the week preop but not later in the week potentiated postop morphine	3	Parallel design No explanation for this phenomenon given
Postop dental pain	Fluoxetine, 10 mg/day × 7 days, or placebo preop	70/70	No effect on postop pain but antagonism of morphine but not pentazocine	3	Parallel design
Acute low back pain	Amitriptyline, 150 mg Acetaminophen, 2000 mg 5 wk	20 19	Yes Yes		Parallel design Amitriptyline more effective in reducing low back pain intensity after 2 wk
Healthy human volunteers Experimental pain	Venlafaxine, 37.5 mg Placebo Dose × 4 q12h	15/17	No effect on pain during cold pressor test	4	Crossover design Increased tolerance thresholds to electrical sural nerve stimulation and summation May indicate a potential analgesic effect in neuropathic pain
Human experimental pain	Desipramine, 225 mg (mean) Placebo 14 days/arm	12/13	No	4	Crossover design
Acute neuropathic pain	Venlafaxine XR, 75 mg Venlafaxine XR, 150 mg Placebo 8 wk	55/60	No effect on pain intensity	3	Parallel design Effect on hyperalgesia and temporal summation
Acute and chronic postmastectomy pain	Venlafaxine, 37.5 mg/day Gabapentin, 300 mg/day Placebo 10 days	150/150	Yes Equal effects in reducing analgesics, both greater than placebo Venlafaxine reduced pain at 6 mo	5	Parallel design
Cancer Pain
Neuropathic pain in breast cancer	Amitriptyline, 50–100 mg/day 4 wk	15/20	Yes	3	Crossover design
Neuropathic cancer pain	Amitriptyline, 30–50 mg/day 2 wk	15/16	No	4	Crossover design
Neuropathic pain in breast cancer	Venlafaxine, 37.5–75 mg 10 wk	13/15	No	4	Crossover design
Arthritis
Osteoarthritis (12) Rheumatoid arthritis (13)	Dibenzepin, 80 mg 3 mo	25/31	Yes	4	Parallel design suggested an interaction with analgesics or antidepressant effect as mode of action
Arthritis	Imipramine, 75 mg 3 wk	22/24	Yes	4	Crossover design Thought to be due to effect on mood
Osteoarthritis Rheumatoid arthritis Ankylosing spondylitis	Imipramine, 25–50 mg 4 wk	55/65	Yes	3	Multicenter, crossover design; 48% improvement in pain vs. placebo
Rheumatoid arthritis and depression	Trimipramine, 25–75 mg 12 wk	27/36	Yes	4	Parallel design; only depressed patients’ pain reduced with no change in depression rating scales
Rheumatoid arthritis	Amitriptyline, 1.5 mg/kg/day Desipramine, 1.5 mg/kg/day Trazodone, 3.0 mg/kg/day Placebo 32 wk (7 wk/arm)	47/73	Yes for amitriptyline only	4	Crossover design; only amitriptyline relieved pain No effect on mood
Rheumatoid arthritis	Dothiepin, 75 mg, plus Ibuprofen, 1200 mg 4 wk	50/60	Yes only at wk 5	4	Parallel design; thought to be an antidepressant effect
Rheumatoid arthritis	Dothiepin, up to 150 mg 12 wk	27/48	Yes from wk 5–12	4	Parallel design; only depressed or anxious patients Analgesic effect separate
Osteoarthritis of the knee	Duloxetine, 60–120 mg/day 13 wk	173/231	Yes	5	Parallel design 15% had 30%+ relief over placebo 18% had 50%+ relief over placebo No difference in adverse events
Fibromyalgia
	Amitriptyline, 25 mg Naproxen, 1000 mgm Both drugs Placebo	58/62	Yes No Yes No	3	Parallel design No significant difference between amitriptyline and both drugs
	Citalopram, 40 mg Placebo	42/43	No	3	Parallel design
	Amitriptyline, 25 mg Fluoxetine, 20 mg Both drugs Placebo	19/31 19/31 19/31 19/31	Yes Yes Yes	5	Crossover design Combination of drugs better than either alone
Hannonen et al 1998	Amitriptyline, 25–37.5 mg Moclobemide, 450–600 mg Placebo	92/130	Amitriptyline superior to placebo but not moclobemide	4	Parallel design 74% responded to amitriptyline vs. 54% to moclobemide and 49% to placebo No difference in dropouts
	Amitriptyline, 50 mg Imagery placebo	17	No	4	Drug dose low at 50 mg
	Amitriptyline, 25 mg Nortriptyline, 25 mg Placebo	40 38 40	No except patient global improvement	5	Parallel design; no difference except in patient global improvement for amitriptyline vs. placebo Dose of drugs was low at 25 mg High placebo response rate
	Duloxetine, 60 mg bid, vs. placebo 12 wk	124/207	Yes with or without depression	4	Parallel design Significant number (30.3%) of females treated with drug had 50% relief or better on FIQ than with placebo (16.5%) No significant difference in severe adverse events
	Duloxetine, 60 mg/day Duloxetine, 60 mg bid Placebo 12 wk	216/354	Yes for both duloxetine doses	3	Parallel design 30%+ reduction in BPI pain scores in 54% with 60 mg/day, in 55% with 120 mg/day, and in 33% with placebo NNQ for 66 subjects: 21.2% with 60 mg/day, 23.3% with 120 mg/day, and 11.7% with placebo
	Paroxetine or placebo 12 wk	86/116	More (57%) taking paroxetine showed 25% reduction in FIQ than with placebo (33%)	5	Parallel design
	Duloxetine, 20, 60, and 120 mg/day, or placebo 6 mos	278/520	Yes for 120 mg/day	4	Parallel design NNT for 30%+ on BPI severity scale was 10, 7, and 7 for 20/60, 60, and 120 mg/day
	Milnacipran, up to 200 mg qd or 100 mg bid, or placebo 3 mo	90/125	Yes with and without depression	5	Parallel design “Similar effect size as TCAs” 44% of non-depressed and 33% of depressed group had 50% pain relief 14.4% dropout rate due to adverse effects
	Milnacipran, 100 or 200 mg/day, or placebo 15 wk	811/1196	Yes for both doses	5	Parallel design PGIC “much improved” in 48.3% with 100 mg/day, in 51% with 200 mg/day, and in 32.9% with placebo Adverse effect caused dropout rate of up to 23.7% with 200 mg/day
	Milnacipran, 100 or 200 mg/day, or placebo 27 wk	512/888	Yes for both doses	3	Parallel design Composite responder rate for 30%+ was 45.2% for 200 mg/day, 43.8% for 100 mg/day and 27.9% for placebo Dropout rate of up to 27% (with 200 mg/day)
	Duloxetine, 60 or 120 mg/day 52 wk	195/307	No difference between doses, no placebo	4	Parallel design High dropout rate
	Milnacipran, 200 mg/day, or placebo 17 wk	678/884	Yes	3	Parallel design Pain responder rate for 30%+ was 38.6% for drug and 30% for placebo Dropout rate was 22.3% for drug
Headache
	Amitriptyline, 25 mg Amitriptyline, 10 mg Placebo 4 wk	19/30 23/30 16/30	Better Best	4	Parallel design Amitriptyline, 10 mg, better than 25 mg and both better than placebo Suggested dropouts at higher-dose study accounted for lesser effect No difference if dropouts excluded
Migraine	Amitriptyline (average, 30–40 mg) Placebo 27 wk	20/20	Yes	3	Parallel design 16/20 taking amitriptyline had reduced frequency, duration, and severity of attacks
“ Tension headache ”	Fluoxetine, 40 mg od Placebo 4 wk	16/16	Yes	3	Crossover design “Enriched involvement” group all entered had responded to doxepin
	Mianserin Placebo	34/38	Yes	3	Parallel design; mianserin described as anti-serotonergic agent
Migraine and tension headache	Migraine Mianserin, 30 mg Clonidine, 0.15 mg Placebo Tension headache Mianserin, 30 mg Clonidine, 0.15 mg Placebo	20 20	Yes No Yes No	2	Parallel design Mianserin described as α ₂ -blocking drug that potentiates noradrenaline
Ziegler et al 1987 Migraine	Amitriptyline, 50–150 mg Propranolol, 80–240 mg Placebo 4 wk on each	30/54	Yes	3	Crossover design Both drugs equally superior to placebo
Chronic daily headache (64) and migraine (58)	Migraine Fluoxetine, 40 mg Placebo Chronic daily headache Fluoxetine, 40 mg Placebo	54/58 60/64	No Yes	4	Parallel design Fluoxetine, a serotonergic drug, effective only for frequency not severity of chronic daily headache “Modest improvement”
Medication-induced headache “ Non-depressed ”	Amitriptyline, 75 mg Active placebo pill Trihexyphenidyl, 2 mg 4 wk	17	Yes	5	Parallel design Improvement in headache frequency and QOL with amitriptyline All withdrawn from analgesics abruptly
Migraine	Venlafaxine, 75 mg Venlafaxine, 150 mg Placebo 2 mo	49/60	Yes for venlafaxine, 150 mg/day	3	Parallel design Reduced number of headache attacks for venlafaxine, 150 mg/day, vs. placebo Adverse effects: 5.9% with placebo, 13.3% with 75 mg/day, 11.6% with 150 mg/day; nausea and vomiting most common
Tension-type headache	Venlafaxine XR, 150 mg/day Placebo 12 wk	40/60	Yes	4	Parallel design Decline in headache days NNT 50% = 3.48 NNQ = 5.58 Most common: GI upset in up to 15% and dizziness in 9%
Migraine	Topiramate, up to 100 mg/day Amitriptyline, up to 150 mg/day Combination of both No placebo 12 wk	63/75	No difference in primary outcome of mean migraine frequency, severity, and duration		Parallel design With combination greater satisfaction, less depression, lower dose of amitriptyline, and fewer side effects
Migraine	Topiramate, up to 100 mg/day Amitriptyline, up to 100 mg/day No placebo 26 wk	197/347 ITT = 331	No difference in primary (monthly migraine episodes) or secondary outcomes	5	Parallel design Non-inferiority Excluded non-responders to both drugs Adverse events in 66.7% with topiramate and in 66.3% with amitriptyline; most common: paresthesias, fatigue, somnolence, and nausea with topiramate and dry mouth, fatigue, and somnolence with amitriptyline
Low Back Pain
	Imipramine, 75 mg 4 wk	44/59	No	3	Parallel design
	Imipramine, 150 mg 8 wk	41/50	No effect on pain	4	Parallel design Possible role for imipramine in low back pain
	Trazodone Mean = 201 mg	42	No	3	Parallel design Serotonergic agent
“ Rheumatic pain conditions ” Low back pain (27) Osteoarthritis (16) Fibromyalgia (8) Rheumatoid arthritis (8)	Fluoxetine, 20 mg Amitriptyline, 25 mg Placebo 4 wk	59	Yes, both effective but fluoxetine better than amitriptyline	3	Parallel design Fluoxetine more effective with fewer side effects
Non-depressed patients	Nortriptyline, 100 mg Inert placebo 8 wk	57/78	Yes	4	Parallel design Noradrenergic mechanisms thought relevant to analgesia in low back pain
	Paroxetine, 20 mg	61/92	No	4	Parallel design No effect of paroxetine on pain or depression
Chronic low back pain	Bupropion, 150–300 mg/day, or placebo 16 wk	44/54	No	5
Chronic back pain	Duloxetine, 20, 30, or 120 mg/day, vs. placebo 13 wk	267/404	No (at end point)	5	Parallel design
Chronic low back pain	Duloxetine, 60–120 mg/day, or placebo 13 wk	213/236	Yes	3	Parallel design 38.5% with duloxetine vs. 27% with placebo had 50% relief
Miscellaneous Chronic Pain Disorders
Women with chronic pelvic pain × 3 mo	Sertraline, 100 mg Placebo 6 wk	23/25	No	4	Crossover design
Non-cardiac chest pain	Sertraline, 50–200 mg Placebo	30/30	Yes	4	Parallel design; in single-site intent-to-treat analysis, greater reduction in pain with drug No change in Beck Depression Scale scores
Prostadynia	Fluvoxamine, median of 150 mg Placebo 8 wk	13/42 16/42	Yes	5	Parallel design ITT reduction in pain independent of antidepressant effect 8 dropouts with drug
Burning mouth syndrome × 6 mo	Trazodone, 100–200 mg Placebo 8 wk	11/18 17/19	No	5	Parallel design Large dropout rate due to side effects
“ Chronic pain ”	Amitriptyline, 150 mg Placebo 6 wk	32/52	No	3	Crossover design Patients with “somatic pathology” excluded
“ Chronic pain” × 3 mo	Zimelidine, 300 mg Placebo 6 wk	20/21	No	3	Crossover design Zimelidine superior only in investigator global assessment but not by patient VAS
Chronic facial pain × 6 mo ; “ most had evidence of musculoskeletal pain ”	Amitriptyline, 30–150 mg Placebo 4 wk/arm	28/32	Yes	4	Both high- and low-dose groups responded within group parallel design No dose response Efficacy independent of effect on depression
Non-cardiac chest pain	Paroxetine, up to 50 mg/day, or placebo 8 wk	43/50	No effect on pain	4	Parallel design
Post-herpetic Neuralgia
	Amitriptyline, 75 mg (median), vs. placebo (inert) 3 wk	24	Yes	3	Crossover design Independent analgesic effect described
	Amitriptyline, 65 mg (mean), vs. lorazepam vs. placebo (inert) 6 wk	41/58	Yes	4	Crossover design No effect of the benzodiazepine lorazepam
	Desipramine, 167 mg (mean), vs. placebo (benztropine) 6 wk	19/26	Yes	4	Crossover design
	Amitriptyline, 100 mg (median), vs. maprotiline, 100 mg (median) (no placebo) 5 wk	32/35	Yes	4	Crossover design; no placebo Both drugs appeared effective but maprotiline less than amitriptyline
	Amitriptyline, 58 mg (mean), vs. nortriptyline, 75 mg (mean) 5 wk	31/35	Yes	4	Crossover design; no placebo Nortriptyline had less severe adverse events
	Amitriptyline, 12.5–200 mg, vs. fluphenazine, 1–3 mg, vs. active placebo (glycopyrrolate) 8 wk	49/49	Yes	4	Crossover design No effect from addition of fluphenazine
	Nortriptyline, 89 mg (mean) Desipramine, 63 mg (mean) Morphine Methadone 8 wk	44/70	Yes	5	Crossover design; both tricyclics and opioids effective Trend favoring opioids Different mechanisms suggested for TCAs and opioids
TCA-naïve post-herpetic neuralgia	Desipramine, 150 mg Amitriptyline, 150 mg Fluoxetine, 60 mg np placebo	38/47 13/21 desipramine 15/17 amitriptyline 10/15 fluoxetine	Yes for all three drugs		Parallel design No difference in daily pain intensity or relief Moderate-plus relief in 9/17 (53%) with amitriptyline, in 12/17 (80%) with desipramine, and in 5/15 (30%) with fluoxetine
	Nortriptyline, up to 75 mg/day, or gabapentin, up to 2700 mg/day 9 wk	70/76	Equally efficacious for pain but gabapentin better tolerated	5	50%+ relief in 25% with nortriptyline and in 21% with gabapentin One dropout with nortriptyline due to adverse effect of urinary retention
Painful Diabetic Neuropathy
	Imipramine, 50–100 mg, vs. placebo 5 wk	12/15	Yes	4	Crossover design Small study; inert placebo ?Type I error ?Failure of blinding
	Nortriptyline, 50–60 mg, plus fluphenazine, 1–3 mg, vs. placebo 30 days	18/25	Yes	4	Crossover design Included fluphenazine
	Amitriptyline, 116 mg in phase I, 69 mg in phase II, vs. active placebo (benztropine, diazepam) 6 wk	29/37	Yes	4	Crossover design Independent analgesic effect described
	Imipramine, 125–200 mg 3 wk	9/13	Yes	4	Crossover design Small study; inert placebo ?Type I error ?Failure of blinding
	Paroxetine, 40 mg Imipramine, 50–75 mg 2 wk	19/29	Yes Yes	4	3-way crossover Serotonergic drug effect found (paroxetine) Imipramine more effective than paroxetine
	Clomipramine, 50–75 mg, vs. desipramine, 50–100 mg 2 wk	19/26	Clomipramine relieved pain	3	Crossover design; small study Serotonergic drug effect Desipramine not shown to relieve pain, only paresthesias
Sindrup et al 1992	Citalopram, 40 mg, vs. placebo 3 wk	15/18	Yes, a slight effect	3	Crossover design; small study Serotonergic drug effective; “a slight effect”
	Mianserin, 60 mg, vs. imipramine, 25–350 mg, vs. placebo 2 wk	18/22	Only imipramine effective	4	Crossover design No effect of mianserin (serotonergic)
	Desipramine, 201 mg (mean), vs. placebo (benztropine) 6 wk	20/24	Yes	3	Crossover design Desipramine effective (noradrenergic)
	Amitriptyline, 105 mg (mean), vs. desipramine, 111 mg (mean), vs. fluoxetine, 40 mg (mean), vs. placebo (benztropine) 6 wk	38/57 38/57 46/57 46/57	Yes Yes No No	3	2-period crossover No effect with fluoxetine (serotonergic) Amitriptyline = desipramine; therefore, noradrenergic effect suggested No antidepressant effect
	Amitriptyline, 75 mg, vs. maprotiline, 75 mg, vs. placebo 4 wk	33/37 19 = PDN	Yes Yes	4	No placebo arm 19 = diabetic, 18 = non-diabetic neuropathy Amitriptyline more effective than maprotiline No difference between diabetic/non-diabetic
	Amitriptyline, 59 mg (mean), vs. gabapentin, 1565 mg (mean) 6 wk	22/25 22/25	Yes Yes	4	Crossover design No difference between amitriptyline and gabapentin in pain relief or adverse events
	Venlafaxine extended release, 75 mg or 150–225 mg, or placebo	202/245	Yes for higher dose	5	NNT for 150–225-mg dose was 4.5 at wk 6 14 dropouts with drug vs. 3 with placebo
	Duloxetine, 20, 60, or 120 mg/day, or placebo 12 wk	344/457	Yes	4	All doses had 50%+ relief vs. placebo: 26% with placebo, 41% with 20 mg, 49% with 60 mg, 52% with 120 mg/day Dropout rate up to 19.5% due to adverse effects (120 mg/day)
	Duloxetine, 60 mg/day or 60 mg bid, or placebo 12 wk	296/348	Yes for both doses	5	50% reduction in “24-hour pain response rate” in 30% with placebo, in 50% with 60 mg, in 39% with 60 mg bid Adverse effect: dropout rate of up to 12.1% with 60 mg bid
	Duloxetine, 60 mg/day or 60 mg bid, or placebo 12 wk	248/334	Yes for both doses	4	30% reduction in 42% with placebo, in 63% with 60 mg, and in 69% with 60 mg bid 50%+ reduction in 27% with placebo, in 43% with 60 mg, and in 53% with 60 mg bid Adverse effect: dropout rate of up to 17.9% (60 mg bid)
	Lamotrigine, 50–200 mg/day, amitriptyline, 10-50 mg/day No placebo	22/38	No difference regarding pain relief	4	Crossover design Fewer adverse effects with lamotrigine
	Amitriptyline, 10, 25, and 50 mg qhs, or pregabalin, 75, 150, and 300 mg bid titration No placebo 5 wk	44/51	No difference regarding pain relief		Crossover design Less frequent adverse effects with pregabalin
Pfizer protocol 1008-040 from FDA website (unpublished)	Amitriptyline, 75 mg/day Pregabalin, 600 mg/day Placebo	188/256	Amitriptyline but not pregabalin superior to placebo	3	Parallel design 50%+ relief in 46% with amitriptyline, in 40% with pregabalin, in 30% with placebo
Other or Mixed Neuropathic Pain
Central pain	Amitriptyline, 75 mg, vs. carbamazepine, 800 mg, vs. placebo 4 wk	15 15 15	Yes No No	4	Crossover design Amitriptyline but not carbamazepine effect Not an antidepressant effect
Central pain	Clomipramine, 25–100 mg Nortriptyline, 25–100 mg 3 wk	24/39	Yes Yes	3	Crossover design Clomipramine more effective
HIV neuropathy	Amitriptyline, 100 mg, vs. mexiletine, 150 mg, vs. placebo (benztropine) 10 wk	126/145 39 44 43	No No No	4	Parallel design No effect on pain for either drug
HIV neuropathy	Amitriptyline, 75 mg, vs. acupuncture, vs. placebo 14 wk	250	No	4	Parallel design
“ Neuropathic pain ”	Topical doxepin vs. capsaicin vs. doxepin/capsaicin, vs. placebo 4 wk	151/255	Yes Yes Yes No	4	Parallel design 49 dropouts—reason not described
Neuropathic pain	Bupropion SR, 150–300 mg, vs. placebo 6 wk	37/41 18 19	Yes No	4	Crossover design Improved = 73% (vs. 10% with placebo) Much improved = 34% (vs. 5% with placebo) Bupropion well tolerated
Spinal cord injury	Amitriptyline, 50 mg (median), vs. placebo (benztropine) 6 wk	73/84 44 40	No No	4	Parallel design
Cisplatin neuropathy	Nortriptyline, 100 mg, vs. placebo 4 wk	51/56	No No	3	Crossover design Modest effect from nortriptyline in second arm but strong carryover effect
Painful neuropathy	Venlafaxine, 225 mg Imipramine, 150 mg Placebo 4 wk	29/30	Yes	5	Crossover design NNT for venlafaxine = 5.2 and for imipramine = 2.7 Both drugs better than placebo
Pain in amputees	Amitriptyline, 10–125 mg/day, or active placebo (benztropine) 6 wk	37/39	No	4	Parallel design Small study; 18 in amitriptyline and 19 in placebo groups
Neuropathic pain ( diabetic neuropathy, post-herpetic, surgical, or traumatic causalgia )	Topical 2% amitriptyline and 1% ketamine 3 wk	80/92	No	5
Lumbar root pain and chronic sciatica 3 mo	Morphine, 62 mg/day (mean), 15–90 mg/day (range), vs. NT, 84 mg/day (mean), 25–100 mg/day (range), vs. combination, 49 mg/day morphine + 55 mg/day NT (means) vs. placebo 9 wk	28/55	No (NSD for morphine, NT, or combination)	5	4-period crossover Moderate or greater relief with morphine in 42%, with NT in 40%, with combination in 62%, and with placebo in 37%; NNH of 10 for morphine, 30 for NT, 11 for combination High dropout rate
Spinal cord injury 6 mo+	AT, 150 mg/day max, GP, 3600 mg/day max, diphenhydramine (active placebo), 75 mg/day 8 wk/period; 3-period crossover	22/38	Yes (SSD)	5	3-period crossover AT more effective than placebo, GP = placebo 30% relief in 62.5% with AT, in 12.5% with GP, and in 25% with placebo
Chemotherapy-induced neuropathy	AT, up to 50 mg/day, vs. placebo 12 wk	33/44	No	5	Small study: 17 with AT vs. 16 with placebo Low dose (max 50 mg/day)
Neuropathic pain ( post-herpetic, diabetic neuropathy post-surgical causalgia ) 6+ mo	Topical amitriptyline vs. lidocaine or placebo 1-wk 3-period crossover with 1-wk washout between	30/35	No	5	Short treatment period
Diabetic neuropathy, post-herpetic neuralgia 6+ mo	NT target: 100 mg/day; max tolerated, 61.6 mg/day monotherapy and 51.5 combination GP target: 3600 mg/day; mean max tolerated, 2433 mg/day with monotherapy vs. 2180 mg/day with combination 18 wk	45/56	Combination therapy more effective than monotherapy with lower doses	5	Crossover design At least moderate relief: 65% with GP, 76% with NT, 84% with placebo (NSD) No difference in adverse effects, none serious
Painful neuropathy 6+ mo	Escitalopram, 20 mg/day, vs. placebo 5 wk/arm of crossover	41/46	Escitalopram better than placebo but a clinically relevant effect in only a few	5	Crossover design Clinically relevant effect in only a few NNT = 6.8
Chronic postmastectomy pain	Venlafaxine, 37.5 mg/day, vs. GP, 300 mg/day, vs. placebo 10 days preop and postop Postmastectomy pain at 6 mo	150/150	Only venlafaxine reduced chronic postmastectomy pain at 6 mo	5

AT, amitriptyline; BPI, brief pain inventory; FDA, Food and Drug Administration; FIQ, Fibromyalgia Impact Questionnaire; GI, gastrointestinal; GP, gabapentin; HIV, human immunodeficiency virus; ITT, intent to treat; NNH, number needed to harm; NNQ, number needed to quit; NNT, number needed to treat; NSD, no significant difference; NT, nortriptyline; od, once per day; PDN, painful diabetic neuropathy; PGIC, patient global impression of change; qhs, every night; QOL, quality of life; SSD, statistically significant difference; TCA, tricyclic antidepressant; VAS, visual analog scale.

Table 34-2

Oral Antidepressant Drugs and Reported Trial Results ^∗

DRUG AND TYPE	RESULT		TOTAL
DRUG AND TYPE	Favorable	Unfavorable	TOTAL
Amitriptyline, TCA	29	13	42
Nortriptyline, TCA	8	2	10
Imipramine, TCA	7	2	9
Duloxetine, SNRI	9	1	10
Fluoxetine, SSRI	5	2	7
Venlafaxine, SNRI	7	2	9
Desipramine, TCA	6	6	12
Milnacipran, SNRI	4	0	4
Mianserin, S	2	1	3
Trazodone, S	0	3	3
Maprotiline (tetracyclic)	2	0	2
Dothiepin, S+N	2	0	2
Clomipramine, TCA	2	0	2
Citalopram/Citaloprim ^† SSRI	1	1	2
Escitalopram, SSRI	1	0	1
Sertraline, SSRI	1	1	2
Paroxetine, SSRI	2	2	4
Dibenzepin, S+N	1	0	1
Trimipramine, TCA	1	0	1
Bupropion	1	1	2
Fluvoxamine, SSRI	1	0	1
Zimelidine	0	1	1
Moclobemide, MAOI	0	1	1
TOTAL	93	39	132

MAOI, monoamine oxidase inhibitor; N, noradrenergic; RCT, randomized controlled trial; S, serotonergic; SNRI, serotonin–noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

∗ Some RCTs had two or more antidepressants; therefore, 132 antidepressants were used in 110 RCTs. These randomized controlled trials are, for the most part, comparisons with placebo. They have mostly small numbers and a crossover design. The quality of these trials may vary, but they do meet the criteria as noted in the “Methods” section according to the Jadad score. They are at least 3/5. There are few head-to-head trials. Many of them do not give clinically meaningful data, and their external validity (generalizability to clinical practice) can be questioned since highly selected patients are frequently enrolled. Furthermore, the outcome measures vary from trial to trial and the trials are invariably of short duration (usually less than 12 weeks). The trials simply document the number reported as favorable versus unfavorable by the authors, and no other conclusions can be drawn from this table.

† Citaloprim not recommended for pain due to lack of efficacy and recent data regarding congenital and acquired prolongation of QT interval and risk of arrythmia.

Table 34-3

Number Needed to Treat for 50%+ Relief in Some Neuropathic Pain Conditions ^∗

DRUG	CONDITION			CENTRAL PAIN	COMMENTS
DRUG	Post-herpetic Neuralgia	Diabetic Neuropathy	Painful Neuropathy	CENTRAL PAIN	COMMENTS
Antidepressant
	2.3	3.0		1.7	Systematic review
	2.3	2.4		1.7	Review
	2.1	3.4			Systematic review
			2.6		Systematic review
		3.2			Systematic review
			3.6		Systematic review
Imipramine
			2.7		RCT
		3.2			Systematic review
Venlafaxine
			5.2		RCT
		4.5			RCT
		3.1			Systematic review
			3.1		Systematic review
Duloxetine
		5.3–5.7			Review
		6			Systematic review
		6			Systematic review
Gabapentin
	3.2	3.7			Systematic review
	5.0				RCT
Pregabalin
	3.4				RCT
Oxycodone
	2.5				RCT
		2.6			RCT
Tramadol
			3.4		Review
	4.3				RCT
Lidocaine Patch
			4.4		RCT
Capsaicin
			5.3		Review

RCT, randomized controlled trial.

∗ Caution should be used when interpreting these figures because they involve studies with different experimental designs, numbers of patients, and data analyses.

Pharmacodynamics and Pharmacokinetics

The original reason for treating chronic pain with antidepressants appears to have been for the relief of concomitant depression ( ). A proportion of patients with chronic pain have been shown to be depressed and to have an increased incidence of familial depression and response to TCAs (e.g., , Krishan et al 1985, ). RCTs have demonstrated that relief of pain, as well as depression, occurs with these agents ( , Couch et al 1976, ). Pain relief separate from the antidepressant effect, suggestive of analgesic action, has been reported since the 1960s. Some of these studies were combination studies with a phenothiazine. clearly articulated the idea that this could be an analgesic action independent of the antidepressant effect. Since then, RCTs have repeatedly and clearly demonstrated separation of the analgesic and antidepressant effects ( , , , , ). Pain relief has been noted in depressed and non-depressed patients with chronic pain of various types in these studies (e.g., , , ). The relief may be more rapid in some patients and appears to occur at a lower dose than the antidepressant effect does (Langhor et al 1982, ). An early concept of the mechanism of antidepressant analgesia was that it occurred via pain-inhibiting systems that descend from the brain stem onto the dorsal horn of the spinal cord ( ). This model involved an endorphin link from the periaqueductal gray area to the medullary raphe nucleus and then a serotonergic (S) connection from the raphe to the dorsal horn of the spinal cord. However, another inhibitory system that involves noradrenaline extends from the locus coeruleus in the lateral pons to the dorsal horn. More recently, descending facilitation by an S mechanism has been described (Benarroch 2008). This may explain the lesser or lack of efficacy of selective S drugs such as the SSRIs. RCTs have demonstrated that the selective S drugs are either not effective ( ) or less effective than noradrenergic (N) agents and those with a mixed effect on serotonin and noradrenaline. The N tetracyclic agent maprotiline has been shown to be effective, but comparative trials indicate that it is less effective than amitriptyline (N + S) ( , ).

The more effective antidepressants for chronic pain appear to be desipramine, amitriptyline, and its metabolite nortriptyline. Antidepressants are relatively “dirty drugs” that act on multiple receptors and have multiple effects. It has been suggested that relief of pain might be due to an anxiolytic or a sedative effect, but this seems unlikely. Other actions that could possibly contribute are dopamine potentiation, an anticholinergic effect, an antihistaminic effect, an anti-inflammatory effect resulting from the inhibition of prostaglandin synthetase ( ), an opioid-mediated effect, K ⁺ channel activation, γ-aminobutyric acid type B receptor (GABA _B ) potentiation, reduction of substance P, or a calcium channel blocking action. In light of current thinking, recent attractive ideas are that these drugs may be N -methyl- d -aspartate (NMDA) antagonists or sodium channel blockers.

Animal research suggests that tricyclics act as local anesthetics probably by blocking sodium channels and that amitriptyline, doxepin, and imipramine are superior in this regard ( ). Perhaps these drugs would be better for suppressing shock-like pain from peripheral ectopic foci, but there is no evidence in humans that this is so. Of interest is evidence that the N reuptake inhibition without an S effect potentiates opioid (tapentadol, oxycodone) analgesia ( , , ). In this chapter we focus on the monoamine descending inhibition model and use it to categorize and explain the efficacy of the analgesic antidepressants.

Five classes of antidepressants have been studied for potential utility in managing NP: the TCAs that combine N and S effects, the SNRIs (which have clear clinical utility), the tetracyclic N antidepressant maprotiline (which has shown limited usefulness), MAO inhibitors (effective for depression but not as analgesics), and the SSRIs (often considered the antidepressants of choice because of their low side effect profile). Each antidepressant class varies in pharmacodynamics, and there is pharmacokinetic variability within classes. Of the TCAs, amitriptyline has been the most studied and is the prototypical tertiary amino side chain TCA. Tertiary side chain compounds produce markedly more anticholinergic and sedative effects than do their active secondary amino side chain metabolites. Although any TCA could be used for pain management because all inhibit reuptake of both monoamines, TCAs vary in side effects and tolerability. The three with the most favorable clinical experience are amitriptyline, nortriptyline, and desipramine, and these drugs have a true analgesic effect on NP and FM pain. Amitriptyline was reported to be useful in the management of NP in the 1980s. Secondary amino side chain metabolites of the tertiary amino side chain TCAs have lower side effect profiles than the parent compounds do ( Table 34-4 ). Because of the dose-limiting anticholinergic, sedative, and next-morning sedation side effects of amitriptyline, its secondary amino side chain metabolite nortriptyline was studied and found to be effective with fewer side effects ( ). Desipramine, the secondary amino side chain metabolite of imipramine, was shown to be effective for NP ( ) and has even fewer anticholinergic and sedative side effects than nortriptyline does (see Table 34-4 ). Another RCT demonstrated comparable analgesic efficacy for desipramine and amitriptyline in NP and no effect of the SSRI fluoxetine ( ). Maprotiline, a tetracyclic antidepressant that is a potent noradrenaline reuptake inhibitor with only weak effects on serotonin, has shown some analgesic effectiveness, but in comparative trials it has been less effective than amitriptyline, which inhibits the reuptake of both monoamines ( , ). Thus it appears that inhibition of the reuptake of both norepinephrine and serotonin favors analgesic effectiveness when monoamine reuptake inhibition is used in pain management as a single pharmacological approach.

Table 34-4

Comparison of the Side Effects of Common Tricyclic Antidepressants Used for the Treatment of Pain

Adapted from Lipman AG 1996 Analgesic drugs for neuropathic and sympathetically maintained pain. Clinics in Geriatric Medicine 12:501–515.

DRUGS	RELATIVE ANTICHOLINERGIC EFFECTS	RELATIVE SEDATIVE EFFECTS	RELATIVE NOREPINEPHRINE REUPTAKE INHIBITION	RELATIVE SEROTONIN REUPTAKE INHIBITION	RELATIVE ORTHOSTATIC EFFECTS
Tertiary Amino Side Chain Compounds
Amitriptyline	++++	++++	++	++++	++
Imipramine	++	++	++	++++	+++
Secondary Amino Side Chain Compounds
Nortriptyline	++	++	++	+++	+
Desipramine	+	++	++++	++	+

The pharmacokinetics of the TCAs can influence their side effects, especially morning drowsiness as a result of drug remaining in the body from a previous evening dose. Some of the pharmacokinetic characteristics of the common TCAs used for pain management are shown in Table 34-5 . Drug-of-choice determinations are often patient specific, and pharmacotherapy should be selected to meet the specific needs of a patient based on previous clinical response, co-morbid conditions, and the patient’s ability to tolerate specific side effects. If a patient has concurrent pain and depression, a TCA could be titrated up to full antidepressant doses (150–300 mg daily). However, these doses often lead to discontinuation because of side effects. More commonly, a TCA for pain is given concurrently with a full-dose SSRI for depression. However, the older SSRIs (e.g., fluoxetine) have a cytochrome P450 interaction with TCAs that results in a doubling or trebling of the TCA serum level ( ). This effect is not a problem with some newer SSRIs (e.g., citalopram).

Table 34-5

Comparison of the Pharmacokinetic Characteristics of Common Tricyclic Antidepressants Used for the Treatment of Pain

	AVAILABILITY (ORAL) (%)	% TOTAL PLASMA PROTEIN BOUND	VOLUME OF DISTRIBUTION (L/kg)	HALF-LIFE	DOSAGE RANGE	PLASMA LEVEL (mg/mL)
Tertiary Amines
Amitriptyline	37–59	95	12–16	10–22	75–300	60–220 ^∗
Imipramine	19–35	95	15–31	11–25	75–300	100–300 ^∗
Secondary Amines
Nortriptyline	46–56	92	14–22	18–44	50–200	50–150
Desipramine	51	90	26–42	12–24	75–300	40–160

∗ Parent compound plus active metabolite.

Aggressive pharmaceutical marketing of newer SNRI antidepressants for both NP and FM has created an impression among clinicians that these drugs are the first-line pharmacotherapy for these indications; however, the evidence base does not support this, as will be shown later. SNRI doses are the same for depression and pain management. Therefore, an SNRI at normal doses might be preferred for managing these two disorders when they occur concurrently. Four SNRIs are used as antidepressants in various countries, one of which is an active metabolite of another. The exact mechanism by which SNRIs provide pain relief is not clear, but it is believed to relate to N and S activity in the central nervous system (CNS). Of note, the effectiveness studies of SNRIs indicate less effect than with the TCAs, thus suggesting that TCAs are preferred over SNRIs as analgesics. Venlafaxine is an antidepressant approved by the Food and Drug Administration (FDA) that has shown an analgesic effect in a few RCTs involving headache and NP (see Table 34-1 ). Its active metabolite desvenlafaxine recently became available in North America and appears very similar clinically to the parent compound.

Some comparative pharmacokinetic parameters of SNRIs are presented in Table 34-6 . A systematic review of duloxetine and milnacipran in which comparative efficacy and harm were examined in managing FM elucidated some differences between the two SNRIs ( ). Both SNRIs decreased appetite and caused hyperhidrosis and insomnia. Only milnacipran elevated subjects’ heart rate. Duloxetine was a better mood elevator than milnacipran, and milnacipran was superior in reducing fatigue. Duloxetine caused more diarrhea than milnacipran did.

Table 34-6

Comparative Pharmacokinetic Characteristics of Serotonin–Noradrenaline Reuptake Inhibitors

	ELIMINATION HALF-LIFE (hr)	S:N SELECTIVITY RATIO	DOSE ADJUSTMENT INDICATIONS
Duloxetine	8–17	9	Decrease with severe renal impairment Do not use for severe hepatic impairment
Venlafaxine	3–7	115	Decrease with hepatic or renal impairment
Desvenlafaxine	11	85	Decrease with moderate to severe renal impairment
Milnacipran	8	3	Use with caution with moderate and reduce the dose with severe renal impairment No need for change with hepatic impairment

N, norepinephrine S, serotonin.

RCTs have demonstrated that SSRIs are either ineffective as analgesics ( ) or less effective than N agents and those with a mixed effect on both monoamines. Although most clinical trials have not supported the use of SSRIs as analgesics (as documented later in this chapter), some studies have suggested analgesic activity for certain SSRIs, most notably citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; however, several of these RCTs had small sample sizes and have not been replicated, and it is often not clear how clinically meaningful the results are. Other clinical trials of SSRIs for pain relief have failed to show any separation from placebo.

Methods

A search for RCTs, systematic reviews, and guidelines in PubMed, MEDLINE, PhRMa, and the Cochrane Database of Systematic Reviews was carried out by the authors with the terms antidepressant , acute pain , cancer pain , chronic non-cancer pain , neuropathic pain , fibromyalgia , arthritis , and low back pain . See Appendix A for search details. The FDA website www.fda.gov was searched for unpublished trials. The main focus was on trials published since the previous review in adults and in English from 2004–2010. RCTs were evaluated according to quality ( ). To be included, trials were required to score at least 3 of 5 on this rating scale to ensure a minimum standard of randomization, double-blind conditions, a control group, and accounting for withdrawals. A maximum score of 5 additionally indicated that the RCT described methods of blinding and randomization. Measures such as effect size, percentage of patients with 50% or greater improvement, NNT, NNH, and the number needed to quit (NNQ) were sought in each trial as a means of determining clinical meaningfulness. Particular note was made of comparative RCTs. We excluded trials with sample sizes of 10 or fewer per group and with chronic pain of 2 weeks or less in duration. We excluded trigeminal neuralgia, complex regional pain syndrome type 2, and the use of lithium for cluster headache.

Results

Guidelines, Systematic Reviews, Reviews

Guidelines for the treatment of NP from Canada ( ), Europe ( ), and the United States ( ) are in reasonable concordance and suggest TCAs as a first choice along with gabapentinoids for post-herpetic neuralgia (PHN), painful neuropathies, and central pain; however, the U.S. guidelines also suggest SNRIs as a first-choice option, which is at variance with the other two, where it is a second-tier option. A comparison of the three guidelines ( ) and an update of the U.S. guidelines ( ) are available. Systematic reviews ( ; ; ) have suggested the superiority of TCAs based on NNTs of 2–3. A review of three RCTs of duloxetine for painful diabetic neuropathy (PDN) ( ) found NNTs for 50% or greater improvement of 5.3 and 5.7 for 60 mg/day and 60 mg twice daily. NNQs were 17.5 and 8.8 for 60 mg/day and 60 mg twice daily, respectively. A systematic review ( ) of six RCTs that included 1696 patients treated with duloxetine, three for PDN and 3 for FM, concluded that this drug is equally effective for both conditions, judged by the outcome of 50% relief or better over a period of 12 weeks, and is well tolerated. An NNT of 6 for 50% relief and an NNQ for lack of efficacy of 20 and for adverse events of 15 were determined. Lower NNTs for TCAs (1.1–3.2) and venlafaxine (3.1) were noted. Another systematic review ( ) of RCTs of duloxetine for painful neuropathy and chronic pain concluded that there was moderately strong evidence for doses of 60 and 120 mg daily in treating the pain of diabetic peripheral neuropathy and FM but not for 20 mg daily. Serious side effects were found to be rare, with a 16% dropout rate. No direct comparisons were found with other analgesics, and the NNT for 50% reduction in pain with duloxetine was found to be 8 for FM and 6 for diabetic neuropathy in the short term (in RCTs of up to 12 weeks). A review from Eli Lilly ( ) of six short-term RCTs of duloxetine for major depression reported discontinuation by 44.3% of patients because of emerging adverse events (versus 22.9% with placebo), and most had mild to moderate adverse events with no increase in pain with extended treatment beyond 9 weeks. Gradual withdrawal was recommended. A review of antidepressants for LBP ( ) concluded that there was no clear evidence that antidepressants are more effective than placebo for this problem. A review of antidepressants for NP ( ) included 61 RCTs and reported NNTs for moderate pain relief of 3.6 for TCAs and 3.1 for the SNRI venlafaxine. It noted the negative RCTs of TCAs for human immunodeficiency virus (HIV)-related neuropathy. NNQ values of 28 for amitriptyline and 16.2 for venlafaxine were reported in RCTs. No data for duloxetine or milnacipran were available. A review of drugs for NP ( ) provided evidence of relief of various NP conditions by TCAs and noted a recent favorable study on the central pain of spinal cord injury but also negative RCTs of amitriptyline for HIV neuropathy and of this drug and nortriptyline for chemotherapy-induced neuropathy. Favorable RCTs of duloxetine and venlafaxine for painful polyneuropathy were noted, but also failure of venlafaxine for the NP of breast cancer ( ). SSRIs were found to be weak analgesics in a few RCTs. These authors concluded that despite a 66% increase in RCTs since their 2005 article, there was no reason to change their previous algorithm for NP, which documented better NNTs for TCAs and opioids than for SNRIs and SSRIs.

Studies of Historical Importance and Randomized Controlled Trials

Uncontrolled studies of historical importance were found in the French literature ( , , ) and in English ( , , , ). A total of 110 RCTs on pain therapy were identified as meeting our criteria, with 36 added since the previous edition of this volume and one ( ) appearing twice in Table 34-1 because outcomes were for acute and chronic postmastectomy pain. Ten trials involved acute pain; 3, NP cancer pain; 52, chronic non-cancer, non-neuropathic pain; and 46, NP. Favorable trials were found in 3 of 10 for acute pain (acute LBP), 1 of 3 for cancer pain, 8 of 8 for arthritis, 12 of 12 for headache, 12 of 15 for FM, 3 of 8 for LBP, and 3 of 8 for a miscellaneous group. With NP, 36 of 46 trials were favorable for at least one antidepressant (PHN, 9/9; PDN, 17/17) and 9 of 18 in the “other or mixed neuropathic” category. Amitriptyline was the most studied drug (see Table 34-2 ) and was favorable in 29 of 42 trials, followed by nortriptyline (8/10); imipramine (7/9); duloxetine (9/10); fluoxetine (5/7); venlafaxine (7/9); desipramine (6/12); milnacipran (4/4); paroxetine (2/4); mianserin (2/3); maprotiline (2/2); dothiepin (2/2); clomipramine (2/2); citalopram, escitalopram, dibenzepin, trimipramine, and fluvoxamine (all 1/1); and sertraline and bupropion (both 1/2). Unfavorable trials were found with trazodone (3/3), zimelidine (1/1), and moclobemide (1/1). Some trials studied more than one antidepressant and hence there are 132 drugs in the 110 trials. Nineteen antidepressant RCTs for chronic pain were comparisons with other antidepressants and 18 were comparisons with other analgesics. Forty-three trials were crossover in design and 57 were parallel, and 30 of 43 of the crossover studies involved NP. The median number of patients entering crossover trials was 45 (13–73), and the median number for parallel trials was 56 (28–1196). Most trials had small numbers of patients, and the crossover design was used successfully in many studies of NP with no major problem with carryover effects.

Acute Pain

Ten RCTs of antidepressants used in the setting of acute pain were identified (see Table 34-1 ). Neither desipramine nor amitriptyline was effective, but desipramine increased and prolonged morphine analgesia in patients undergoing tooth extraction ( ). No effect on acute pain from hip or knee arthroplasty was found with 50 mg of amitriptyline for 3 days postoperatively ( ) or desipramine on the first postoperative day ( ). Desipramine potentiated the action of morphine in dental extractions if given early preoperatively (7 days) but not later (3 days) ( ). Fluoxetine did not affect postoperative pain in dental surgery but antagonized morphine and not pentazocine postoperatively ( ). Amitriptyline was more effective than acetaminophen for acute LBP ( ). Venlafaxine and desipramine had no effect on human experimental acute pain ( , ). Venlafaxine was not found to have any effect on capsaicin-induced allodynia and hyperalgesia in acute human experimental pain ( ). Perioperative administration of venlafaxine, 37.5 mg/day, gabapentin, 300 mg/day, or placebo for acute and chronic postmastectomy pain resulted in the finding of equal effects in reducing analgesic requirements, with gabapentin being more effective in reducing acute pain after movement and venlafaxine more effective in reducing chronic postmastectomy pain at 6 months ( ).

Cancer Pain

Three trials of antidepressants for cancer pain were identified, all with NP (see Table 34-1 ). Amitriptyline, 50–100 mg/day, reduced NP in breast cancer ( ). There was no such benefit with amitriptyline, 30–50 mg/day, for NP in a more general group of cancer patients ( ). No significant effect of venlafaxine was noted for NP in breast cancer ( ).

Chronic Non-cancer, Non-neuropathic Pain

Fifty-two RCTs of chronic non-cancer, non-neuropathic pain that met the minimum criteria for inclusion were identified (see Table 34-1 ). These disorders included arthritis (8), FM (15), headache (12), LBP (9), and a miscellaneous group (8). A total of 37 of 52 trials and 40 drugs (some RCTs were comparative) were favorable. Of these studies, 8 of 8 were favorable for arthritis, 12 of 15 for FM, 12 of 12 for headache, 3 of 9 for LBP, and 3 of 8 for the miscellaneous group (favorable trials involved chest pain, prostadynia, and chronic facial pain). Antidepressants associated with a favorable result were amitriptyline (12), duloxetine (6), milnacipran (4), fluoxetine (4), venlafaxine (2), dothiepin (2), mianserin (3), imipramine (2), fluvoxamine (1), nortriptyline (1), dibenzepin (1), sertraline (1), and trimipramine (1). Thus, selective and non-selective S and N drugs showed an effect in this group of chronic pain disorders. It was not possible in most of the favorable trials to tell how clinically meaningful the results were (no details were given regarding effect size or NNT). Exceptions were six RCTs of duloxetine for diabetic neuropathy and FM, for which the NNT was 6 ( ).

Neuropathic Pain

NP may be defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. It may occur in the peripheral nervous system (peripheral neuropathic pain) or in the CNS (central pain) ( ).

Antidepressant therapy is one of the oldest, scientifically proven treatments of NP. Its use was based on uncontrolled data from as early as the 1960s and often included combination therapy with a phenothiazine. An RCT in 1982 showed that amitriptyline alone was superior to placebo ( ). Since then, many other RCTs have followed and some of these drugs remain as standard therapy. Although the focus here is on RCTs, there is a failure in previous reviews to credit the early less vigorous uncontrolled and survey studies, which are the foundation of our current science. Other reviews omit head-to-head trials if there is no placebo arm. Most of the research has been done in PHN and PDN, and the results are quite similar except for some evidence of an effect of S agents in the latter. (See also Table 34-1 for three randomized controlled trials of neuropathic pain in cancer.)

Randomized Controlled Trials of Neuropathic Pain

Forty-six RCTs of antidepressants for non–cancer-related NP were identified that met our criteria (see Table 34-1 ). Nineteen were conducted for PDN, 9 for PHN, and 18 for other NP conditions, including central pain (2), HIV-related neuropathy (2), cisplatin-induced neuropathy (1), painful polyneuropathy (2), chemotherapy-related neuropathy (1), sciatica (1), spinal cord injury (2), phantom pain (1), postmastectomy pain syndrome (1), and mixed NP (PHN, diabetic neuropathy, causalgia) (5). Three of the studies involved topical preparations (doxepin, amitriptyline) and the rest consisted of a variety of oral antidepressants. Of the trials of drugs with an effect on both serotonin and norepinephrine, 15 were favorable with amitriptyline, 5 with imipramine, 3 with duloxetine, 3 with venlafaxine, and 2 with topical doxepin. Thus, 27 were favorable with drugs having this mixed effect. With more N agents 13 were favorable (nortriptyline, 6; desipramine, 4; maprotiline, 2; and bupropion, 1). Drugs with a predominantly S effect were positive in 6 instances (paroxetine, 1; fluoxetine, 1; clomipramine, 2; citalopram, 1; and escitalopram, 1). It was difficult to determine how clinically meaningful the results of these S trials were. Twenty-three of the RCTs involving NP were head-to-head comparisons, and hence there are more drugs tabulated than trials.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here