Treating Chronic Pain with SSRIs: What Do We Know?

Table 1

(a) Data extracted from the randomized placebo-controlled double blind trials included for review. (b) Data extracted from other trials included for review.

(a)

Reference	Blinded	Randomized	Cross-over	Placebo	Pain condition	Number of patients	SSRI	Total trial duration (in weeks)	Measured pain outcome	Reported results
[38]	Double	Yes	No	Yes	Fibromyalgia	40	Citalopram	20	Pain perception and Fibromyalgia Impact Questionnaire (FIQ)	After two months with citalopram treatment there was a significant decrease on pain outcomes (). After four months of treatment the effect diminished (being nonsignificant).
[41]	Double	Yes	No	Yes	Fibromyalgia women	60	Fluoxetine	12	Fibromyalgia Impact Questionnaire and pain intensity score	Pain intensity mean change from baseline to endpoint was −8.6 ± 14.5 for fluoxetine group and 2.9 ± 13.6 for placebo ().
[16]	Double	Yes	No	Yes	Chronic lower back pain	103	Paroxetine	8	Pain intensity	There was a 45% decrease in pain intensity on maprotiline, compared to 27% decrease in placebo, and 26% decrease on paroxetine. The mean reduction in pain intensity on paroxetine compared to placebo was not significant ().
[34]	Double	Yes	Yes	Yes	Chronic tension type headache	40	Citalopram	24	Intensity and duration of headache	During placebo, headache outcome decreased by 10% compared with baseline (). Pain outcome was 30% lower during amitriptyline when compared to placebo () and 20% when compared to citalopram ( after Bonferroni correction).
[49]	Double	Yes	No	Yes	Noncardiac chest pain	50	Paroxetine	8	Pain intensity rating	Paroxetine treated patients showed greater improvements than placebo () on the Clinical Global Impressions scale.
[29]	Double	Yes	Yes	Yes	Women with chronic pelvic syndrome	33	Sertraline	12	Pain intensity	Composite pain intensity score after sertraline 2.7; pain intensity after placebo 2.7^#.
[43]	Double	Yes	No	Yes	Migraine without aura	52	Fluoxetine	28	Total pain index (TPI)	TPI was significantly reduced after fluoxetine treatment (41.3 ± 63.8) compared to start point (135 ± 115.8; ).
[17]	Double	Yes	No	Yes	Low back pain	92	Paroxetine	8	Pain intensity	No significant effect on pain intensity between paroxetine (57 ± 23.8) and placebo (57 ± 24.3).
[22]	Double	Yes	Yes	Yes	Chronic pain (variety)	21	Zimelidine	12	Self-rated pain intensity and doctor’s pain global assessment	Self-rated pain intensity after 6 weeks of zimelidine treatment 45.7 ± 24.6 and after placebo treatment 45.0 ± 27.0. There was a statistical significant difference in global assessment between zimelidine and placebo phases on the doctor’s assessment (rate varies between pain conditions).
[42]	Double	Yes	Yes	Yes	Fibromyalgia	31	Fluoxetine	20	Pain intensity and physician evaluation in tender points	Pain intensity at baseline was 68.4 ± 20.4. Pain intensity was significantly decreased after fluoxetine treatment (47.6 ± 19.8) compared to placebo (58.8 ± 17.1; ).
[21]	Double		No	Yes	Chronic pain (variety)	40	Zimelidine		Pain relief and analgesic consumption	Patients’ self-rated pain decreased from 64.9 ± 6.3 at start to 46.8 ± 5.1 after zimelidine treatment (). Patients receiving placebo reported a start pain of 44.8 ± 5.4 and a final pain intensity of 46.6 ± 7.8 (nonsignificant change). The physician’s clinical judgment of changes in level of pain showed that 12 patients were considered improved, 9 in zimelidine and 3 in the placebo group ().
[26]	Double	Yes	No	Yes	Noncardiac chest pain	115	Sertraline	34	Pain intensity and unpleasantness	The authors did not mention the raw pain data. However, they analyzed the results in terms of treatment condition × time interaction. The overall analysis was significant for both pain intensity [, ] and unpleasantness [, ]. Groups with coping skill training (CST) + sertraline or sertraline alone resulted in greater reductions in pain intensity and unpleasantness compared to placebo alone.
[45]	Double	Yes	Yes	Yes	Painful diabetic neuropathy	57	Fluoxetine	13	Self-rated pain relief	The mean pain-diary scores decreased by 0.35 ± 0.11 units in the patients consuming fluoxetine and 0.15 ± 0.07 units in patients receiving placebo ().
[50]	Double	Yes	Yes	No	Chronic tension type headache	87	Paroxetine	16	Headache intensity and analgesic consumption	No statistical significance between the effect of paroxetine and sulpiride. Paroxetine improved headache intensity (change in headache −0.4, ) and analgesic consumption (change −0.8, ) when compared to baseline.
[28]	Double	Yes	Yes	Yes	Males with chronic pelvic pain syndrome	14	Sertraline	26	Prostatic symptom severity (PSS) and prostatic symptom frequency (PSF)	PSS at baseline 23.4 and PSS after 13 weeks of sertraline 17.3 (). PSF at baseline 15.9 and PSF after sertraline treatment 12.3 (). No significance between sertraline and placebo treatment (PSF and PSS )^#.
[44]	Double	Yes	No	Yes	Persistent somatoform pain disorder	80	Fluoxetine	8	Medical Outcomes Study Pain Measures (MOSPM)	MOSPM total score after fluoxetine treatment (33.08 ± 18.81) was significantly reduced in comparison with baseline (59.53 ± 22.76; ). Participants receiving fluoxetine had greater reduction in MOSPM total score when compared to placebo (MOSPM 65.75 ± 24.87 at baseline and 55.33 ± 25.44 at endpoint).
[62]	Double	Yes	No	Yes	Multisomatoform disorder	51	Escitalopram	12	Patient Health Questionnaire-15 score (PHQ), pain intensity (VAS)	There was a significant improvement in PHQ in both escitalopram (from 14.6 ± 0.96 to 5.6 ± 1.0, ) and placebo (17.3 ± 0.9 to 12.5 ± 1.0, ) at the end of the trial compared to baseline. There was also a significant difference between placebo (12.5 ± 1.0) and escitalopram group (5.6 ± 1.0, ) at the end of the trial.
[36]	Double	Yes	No	Yes	Fibromyalgia	42	Citalopram	8	Pain intensity and Fibromyalgia Impact Questionnaire (FIQ)	Pain self-assessment for citalopram group at start was 6.3 ± 2 (change −1 ± 2.1) and for placebo group was 6.7 ± 1.9 (change −0,7 ± 1.1). No significant effects were observed between the two groups.
[63]	Double	Yes	Yes	Yes	Painful polyneuropathy	48	Escitalopram	10	Self-rated pain relief	Pain relief after 5 weeks of treatment with escitalopram was higher than during placebo, with a mean of 0.8 ().
[52]	Double	Yes	No	Yes	Fibromyalgia	86	Paroxetine	12	Fibromyalgia Impact Questionnaire (FIQ) total score	Significantly greater proportion of subjects in the drug group responded (56.8%) than in the placebo group (32.7%) regarding reduction in FIQ score ().
[57]	Double	Yes	No	Yes	Chronic prostatodynia	42	Fluvoxamine	8	Pain intensity	The authors did not report the improvements in pain in terms of percentage from baseline. The fluvoxamine-treated group showed significant improvement in pain when compared to placebo group (rank sum 553 at week 8, , ). This significance was observed from week 4 (rank sum 528.5; , ).
[19]	Double	Yes	No	Yes	Chronic daily headache and migraine	122	Fluoxetine	4 (single blind) + 12 (double blind)	Overall headache intensity and frequency	At the end of the trial the fluoxetine group showed a significant effect in headache improvements () compared to placebo. No pain intensity in detail was published.
[53]	Double	Yes	Yes	Yes	Diabetic neuropathy	29	Paroxetine	6	Pain intensity	Pain intensity during placebo 5.79 and in fluvoxamine 1.25 ()^#.
[27]	Double	Yes	No	Yes	Noncardiac chest pain	30	Sertraline	9	Pain intensity	Group 1 initial pain score 3.94; pain score after sertraline treatment 1.47 ().; Group 2 initial pain score 3.50; pain score after placebo 2.96 (); significance difference between placebo and sertraline group ()^#.

(b)

Reference	Blinded	Randomized	Cross-over	Placebo	Pain condition	Number of patients	SSRI	Total trial duration (in weeks)	Measured pain outcome	Reported results
[32]	Double	Yes	No	No	Somatoform pain disorder	35	Citalopram	8	Self-assessed McGill pain questionnaire	In the citalopram group pain scores decreased significantly during the 8-week trial (41.9 ± 17.7 vs 90.0 ± 19.02, ).
[35]	No	No	No	Yes	Women chronic pelvic pain	14	Citalopram	12	McGill pain intensity scale and pain disability index (PDI)	Pain severity showed a nonsignificant trend toward improvement on the McGill pain intensity scale (). There were no significant differences on the PDI ().
[51]	No	No	No	No	Chronic daily headache	60	Paroxetine	12–36	Percentage of headache days	Reduction in number of headache days per month was reported in 38% of patients. No significant analysis was reported.
[37]				No	Painful diabetic neuropathy	101	Paroxetine, citalopram	24	Pain intensity scale (0–4)	In patients who took one of the two SSRIs, 43,5% noticed no effect on the pain control, 50% felt better, and 6,5% felt worse.
[54]	No	No	No	No	Chronic tension type headache	31	Paroxetine	36	Headache index, taking in consideration days per month with headache and analgesic consumption	In patients who did not respond to amitriptyline, paroxetine failed to reduce chronic tension type headache or analgesic consumption (only 15% showed more than 50% reduction in headache index). In patients who did no respond to placebo, paroxetine produced modest reductions in headache index (39% of patients had 50% or higher reduction in headache index).
[56]	Double	Yes	No	No	Chronic tension type headache	40	Fluvoxamine	12	Pain severity and analgesic consumption	Pain intensity at baseline 2.42 and pain intensity after fluvoxamine 0.96 (). There was also a reduction in analgesic consumption ()^#.
[61]	No	Yes	No	No	Chronic lower back pain	85	Escitalopram	13	Physician rated overall pain relief	There was no significant difference between escitalopram and duloxetine group. Significant difference was found when comparing baseline to the end of trial on escitalopram (mean change −2.30 ± 0.33) and duloxetine group (−2.45 ± 0.30).
[46]	Blind-rater	Yes	No	No	Musculoskeletal pain	40	Fluoxetine	6	Pain intensity and pain relief	Moderate or good pain relief was reported by 14 of the 17 patients (82%) in the amitriptyline group and by 14 of the 18 (77%) in the fluoxetine group. Both treatments reduced pain intensity. There was no significant difference between groups.
[58]	No	No	No	No	Central poststroke pain	31	Fluvoxamine	2–4	Pain intensity	Pain intensity at baseline 7.7 ± 2.2 was significantly reduced after fluvoxamine treatment (pain intensity 6.0 ± 3.4, ).
[33]	Double		Yes	Yes	Diabetic neuropathy	17	Citalopram	6	Self-rated neuropathy symptoms	Citalopram significantly relieved the symptoms of neuropathy as measured by both observer rating and self-rating compared to placebo.
[18]	Single	Yes	No	No	Chronic tension type headache	37	Fluoxetine	12	Pain intensity, analgesic consumption, and survey short form 36 (SF36)	Baseline pain 6.6 ± 1.4; pain after fluoxetine 4.2 ± 2.9 (). The number of analgesic tablets taken per week reduced from 20 to 9 ().
[47]	No	No	No	No	Chronic prostatitis	42	Fluoxetine	12	Chronic prostatitis symptom index (CPSI)	Significant decrease in total CPSI score (28.55 to 9.29) and CPSI pain subscore (14.69 to 5.19) was observed 12 weeks after the baseline assessment ().

Standard deviation not reported in the original article.