Antipsychotics for Acute and Chronic Pain in Adults

Article Outline

• Abstract
• Introduction
• Methods
  • Searching
  • Selection
    • Types of Studies
    • Types of Participants
    • Types of Interventions
    • Primary Outcomes
    • Secondary Outcomes
  • Data Collection and Analysis
    • Study Selection
    • Assessment of Quality
    • Data Extraction
    • Data Analysis
• Results
  • Description of Studies
    • Study Selection
    • Study Design
    • Outcomes
    • Study Methods
    • Drugs and Conditions
  • Risk of Bias in Included Studies
  • Effects of Interventions
    • Additional Outcomes
• Discussion
• Conclusions
• Acknowledgment
• References
• Copyright

Abstract 

Context

The role of antipsychotics as adjuvant analgesics is a subject of long-standing controversy. Antipsychotics have been used to treat chronic pain (e.g., chronic headache, fibromyalgia, and painful diabetic neuropathy). With atypical antipsychotics, a new class of antipsychotics, with fewer extrapyramidal side effects and additional benefits, may be available.

Objectives

This review aimed to assess analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain.

Methods

Randomized controlled trials of adults prescribed any dose of oral antipsychotics for acute or chronic pain, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review.

Results

We included 11 studies involving a total number of 770 participants. Data from five randomized, double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Because of the clinical heterogeneity of painful conditions studied and significant statistical heterogeneity, the intended meta-analysis was omitted. The most frequently reported adverse effects were extrapyramidal (i.e., involuntary movements, parkinsonism, and akathisia) and sedating effects.

Conclusion

Because of limitations in the available evidence, further research is needed to understand whether antipsychotics are effective for acute or chronic pain or specific pain conditions.

Key Words: Antipsychotics, pain, neuralgia, dopamine

Back to Article Outline

Introduction 

Antipsychotics (also called neuroleptics) can be classified according to their chemical structure into tricyclic antipsychotics (phenothiazines, thioxanthenes), butyrophenones, substituted benzamides, and other chemical substances (dichlorphenyl-piperazinyl-chiloninones, diphenylbutylpiperidines, benzisoxazoles, benzisothiazylpiperazines, phenylpiperidines). Classic antipsychotics or “first-generation antipsychotics” differ from atypical antipsychotics in that the latter have fewer extrapyramidal side effects, effectiveness in negative symptomatology, and lower prolactin elevations, with comparable antipsychotic efficacy. Classic antipsychotics have a predominant antagonism at the dopamine-receptor type 2 (D₂), whereas the atypical antipsychotics also address other neurotransmitter systems, for example, the serotonin system.

The role of classic antipsychotics as potential adjuvant analgesics has been a subject of longstanding controversy. Their clinical usefulness in the management of pain has been questioned.¹ Neuroleptanalgesia (a state of quiescence, altered awareness and analgesia that may be induced by an opioid analgesic and an antipsychotic) was shown to negatively influence disease course and total mortality in unstable angina patients.²

Nonetheless, antipsychotics have been used in a variety of chronic pain states, from cancer pain³, ⁴, ⁵ to chronic noncancer pain⁶ chronic headache or chronic refractory headache,⁷, ⁸, ⁹ fibromyalgia,¹⁰ musculoskeletal pain,³ low back pain,³, ¹¹ chronic pain in older patients,¹² pain in acquired immunodeficiency syndrome,¹² postherpetic neuralgia,¹³ chronic facial pain,¹⁴, ¹⁵ and painful diabetic neuropathy.¹⁶

In a meta-analysis on the analgesic potency of antipsychotics by Nix,¹⁷ only 10 of 15 studies with a higher statistical study power described a possible analgesic effect. However, none of these studies could differentiate between the effects of analgesia and sedation of the drugs used.

With the arrival of atypical antipsychotics, a new class of antipsychotics, fewer extrapyramidal side effects and potential additional benefits are now available. Hence, a new meta-analysis is needed to address the question of evidence-based therapy of pain with antipsychotics.

Back to Article Outline

Methods 

Searching 

For the identification of studies included or considered for this review, the following databases were searched:

Detailed search strategies were developed for each database searched and can be accessed in the corresponding review at the Cochrane Library.¹⁸

Reference lists from retrieved trials were checked for additional studies. Also, relevant studies cited in reviews identified by searching the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews and Effectiveness were sought.

We contacted the corresponding authors of the identified articles and experts in the field for additional studies. Furthermore, letters requesting information about published or unpublished trials were sent to pharmaceutical companies that manufacture antipsychotics (Sanofi-Synthelabo, France: amisulpride, fluphenazine, sulpiride, tiapride; Lundbeck, Denmark: chlorprothixene, flupentixole decanoate, melperone, sertindole, zuclopenthixole; Novartis, Switzerland: clozapine, thioridazine; Eli Lilly, USA: olanzapine; AstraZeneca, United Kingdom: quetiapine; Janssen-Cilag, United Kingdom: haloperidole, pimozide, risperidone; Asta Medica, Austria: prothipendyl hydrochloride; Knoll Ltd, United Kingdom: zotepine; Pfizer, USA: ziprasidone; Gerot, Austria: levomepromazine; UCB-Pharma, Belgium: dixyrazine).

Selection 

We included randomized controlled trials (RCTs) that were double-blind and that investigated the analgesic effects of antipsychotics as monotherapy or add-on treatment in patients with acute or chronic pain, if pain assessment was either the primary or a secondary outcome. Reports were excluded if they were studies that were nonrandomized, studies of experimental pain, case reports, clinical observations (open studies), or studies of antipsychotics used to treat pain produced by other drugs.

RCTs of adult patients of either gender who had acute or chronic pain, or both, of all degrees of severities, were included in this review.

The evaluated interventions included any form of antipsychotic treatment (at any dose), listed as follows, compared with no treatment, placebo, or other pain-relieving treatments (e.g., nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, opioids). The antipsychotic agents/neuroleptics assessed included amisulpride, amoxapine, chlormethiazole, clopenthixole, chlorpiprazine, chlorpromazine, chlorprothixene, cloxazepine, clozapine, distraneurine, dixyrazine, chlorpromazine, flupentixol decanoate, fluphenazine, haloperidole, levomepromazine, loxapine, melperone hydrochloride, methotrimeprazine, olanzapine, oxilapine, perphenazine, pimozide, prothipendyl hydrochloride, quetiapine, risperidone, sulpiride, thioridazine, tiapride, tisercin, trifluoroperazine, ziprsasidone, zotepine, zuclopenthixole.

The primary outcome measure for this review was the reduction in pain intensity, as measured by a visual analogue scale, self-reported global scale, verbal rating scale, numerical rating scale or categorical pain relief scale and self-reported pain relief. The effectiveness measures after the longest reported duration of treatment were used. Studies that did not quantify pain using a scale were excluded. Patient-reported pain data were included; trials reporting only physician and care-giver pain assessment were excluded.

An assessment of the frequency and severity of the commonly expected adverse effects was undertaken. Adverse effects were classified as minor if they were reported by a participant who continued with the medication and completed the trial. A major adverse effect was defined as one that caused the participant to withdraw from the study.

Additional outcomes included the following:

Data Collection and Analysis 

Two review authors (M.A. and M.O.) independently screened the titles and abstracts of all the references retrieved by the search strategy. The full text of relevant studies was assessed independently to determine whether they met the inclusion criteria. Disagreements were resolved by discussion with the third review author.

Trials that met the inclusion criteria were graded independently for methodological quality and assessed for internal validity using the Jadad Quality Scale score.¹⁹ Each study was allocated a score of between 1 and 5 points. Because the inclusion criteria for this review required trials to be randomized, the minimum quality score was 1. Higher scores indicated a higher quality of conducting or reporting, or both, of the trial. No trial that scored “0” met the inclusion criteria; the minimum score calculated was 2.

The following data items were extracted from each of the included studies, where available:

Data were extracted to a standard form by two review authors independently. Because of possible carry-over effect, only the first phase of crossover studies was used.

Statistical testing of heterogeneity between the trials was carried out using RevMan Analyses 1.0.3 in Meta-View 4.2.8. (clicktime.com, Inc., California, USA) Because of the clinical heterogeneity of painful conditions studied and significant statistical heterogeneity, the intended meta-analysis was omitted.

The quality of included trials was used in exploring any significant statistical heterogeneity between them. Cutoff levels for the subgroup analysis values that were used were “greater or equal to 3” or “less than or equal to 2.”

Back to Article Outline

Results 

Description of Studies 

The original search strategy for the systematic Cochrane review¹⁸ ran in October 2007 and resulted in 1908 hits. The retrieved information about unpublished trials by pharmaceutical companies did not yield further potential data. After screening of the titles and abstracts, 51 potentially relevant studies were identified. Thirty-seven of these 51 studies were excluded (Fig. 1; for full references of excluded studies, please see the work by Seidel et al.¹⁸). Of the excluded studies, 34 did not meet the quality criteria, as assessed by the Jadad Quality Scale, and three high-quality studies were excluded, because the antipsychotics tested (prochlorperazine and droperidole) had not been within the scope of our search strategy. Hence, 14 studies were considered for inclusion in this review. Two of these studies could not be assessed, because a translation into English was not available. For one further study, the study authors could not be identified, and it was, therefore, excluded.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1 

  Trial flow diagram summarizing the stages of the systematic review.

An update of the search strategy in February 2009 produced another 82 hits, including two potentially relevant studies.²⁰, ²¹ Both studies were excluded because the analgesic efficacy of each antipsychotic component was tested against a component without proven analgesic effect.

In sum, 11 RCTs of nine different antipsychotics were considered eligible¹⁴, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹ (n=743) for inclusion in the review (see Table 1 for details on each individual RCT). The sample size ranged from 29 to 316 participants. Most trials were limited by their small sample sizes. Only one trial included more than 200 participants.²³

Table 1. Characteristics of Included Studies

Article	Methods	Participants	Interventions	Outcomes	Notes
Johnston, 197222	Randomized, double-blind, placebo-controlled trial	50 patients—32 outpatients, 18 inpatients, 6 men, 44 women; mean age: 56 years (age range between 31 to 73 years). Inclusion criteria: terminal cancer with a prognosis of at least a 6-week survival. Exclusion criteria: not stated.	Random assignment to either 25mg thioridazine p.o. or placebo 3 times a day (final dose: 75mg) for 3 weeks.	Physician's weekly rating of anxiety/ tension, insomnia, crying spells, fears, anorexia, and withdrawal, overall rating of emotional complaints and pain. Statistically significant changes in the thioridazine group for anxiety/ tension, depressive mood, restlessness, insomnia, crying spells, fears, overall rating of emotional complaints and pain compared with placebo.	Type of pain: cancer pain; 3 dropouts during follow-up. No untoward effects were observed.
Davidsen et al., 197923	Double-blind, controlled, randomized trial	316 patients—mean age: levomepromazine group: 67 years; pethidine group: 68 years. Inclusion criteria: acute myocardial infarction within 24 hours before admission. Exclusion criteria: known adverse reactions to narcotics or phenothiazines, treatment with levomepromazine before admission.	Patients received one injection on admission (50mg pethidine or 12.5mg levomepromazine) and 100mg pethidine or 25mg levomepromazine orally 3 times a day for 3 consecutive days. Further injections were given when needed.	90% of patients encountered pain during the course of the acute myocardial infarction. Recurrences of pain in the first 72 hours were observed in 50% of levomepromazine-treated and in 62% of the pethidine-treated patients (P<0.05). Incidence of nausea was significantly higher in the pethidine-treated group (P<0.001). Until a 1-year follow-up, mortality rates were significantly lower in the levomepromazine-treated group.	Type of pain: pain in myocardial infarction; 3 patients died within 30 minutes after admission; 5 were not treated according to the protocol.
Bussone et al., 198124	Double-blind, placebo-controlled trial	50 patients—40 with mixed headache and 10 with classic migraine. Age range between 17 and 68 years.	Random assignment to either 300mg tiapride or placebo. Duration of treatment: not stated.	Headache intensity, frequency and duration reported by headache diary (including 4 weeks preintervention).	Type of pain: chronic headache; one dropout due to nausea in the treatment group.
Judkins and Harmer 198225	Randomized, double-blind, placebo-controlled trial	34 patients, 18–70 years, both female and male. Inclusion criteria: scheduled for elective major upper abdominal surgery, otherwise fit.	Premedication of either 5 or 10mg haloperidole or placebo.	Analgesic requirement (on-demand system) as measured on a VAS. No significant differences between all 3 conditions regarding the analgesic requirements. Postoperative emesis reduced in the groups receiving haloperidole.	Type of pain: postoperative pain.
Ginsberg et al., 198326	Double-blind, randomized trial	42 patients—16 males, 26 females. Inclusion criteria: definite soft tissue rheumatism, sole location of pain, continuous pain, pain of nonspecific origin. Exclusion criteria: not stated. None had received analgesics for the current affliction before entering the study.	Randomly assigned to 100mg tiapride or 200mg glafenine 3 times daily over a period of 14 days.	Pain intensity (VAS). Initial VAS score: 73mm (tiapride group) and 73mm (glafenine group). VAS score on Day 14: 18.4mm (tiapride group) and 30.4mm (glafenine group). Mild side effects in tiapride group (6 drowsiness, 2 gastric intolerance). No interruption of treatment. By the end of treatment, pain had disappeared in 76% of tiapride-treated and 43% of the glafenine-treated patients.	Type of pain: acute rheumatic pain; no differences between sexes regarding the efficacy rating of the drugs.
Roux et al., 198327	Double-blind, placebo-controlled, randomized trial	30 patients with headache after lumbar puncture (observation period: 48 hours). Inclusion criteria: not stated. Exclusion criteria: not stated.	Random assignment to either 200mg tiapride i.v. or placebo i.v. after rachiocentesis	Occurrence of headache. No headache in 86.7% of patients receiving tiapride and in 46.6% of patients receiving placebo. Statistically significant difference.	Type of pain: post-lumbar puncture headache.
Lechin et al., 198914	Double-blind placebo-controlled, crossover trial. Four-center study	68 patients joined the study. Final number: 48 outpatients, 24 men and 24 women; duration of illness: 8–17 years. Inclusion criteria: severe facial pain for at least 2 years, clinical diagnosis of trigeminal neuralgia. Exclusion criteria: placebo responder (improvement of more than 20% during placebo washout period), severe physical illness, history of psychotic episodes, alcohol or drug addiction, epilepsy, or any other convulsive disorder.	4 weeks of placebo washout, 8 weeks of treatment after random assignment to carbamazepine (final dose of 1200mg with a 14-day titration period) or pimozide (final dose of 12mg with a 14-day titration period), 4 weeks with abrupt withdrawal and placebo substitution, 8 weeks of crossover treatment.	Pain intensity using 6-point registration cards (0=no pain, 6=pain present, cannot be ignored, prompt medical advice sought), duration, frequency, basal pain, sensitivity of trigger zones, number of relief tablets. Total trigeminal neuralgia score reduction of 78.1% (pimozide group) compared with 49.7% (carbamazepine group), statistically significant (P<0.001) at Week 10. Adverse effects (hand tremors, involuntary movements during sleep, slight Parkinson's symptoms) observed in 40 of 48 patients.	Type of pain: trigeminal neuralgia; 9 patients were not admitted to the treatment phase, and 6 patients were excluded. 11 were not included in the statistical analysis. All patients refused interruption of pimozide treatment.
Zitman et al., 199128	Double-blind, placebo-controlled, crossover trial	34 patients—mean age: 34 years. Inclusion criteria: pain duration of at least 6 months, age between 30 and 60 years. Exclusion criteria: severe psychiatric disease; renal, hepatic, or cardiac disorders; epilepsy; glaucoma; hypertension; prostate dysfunction	Baseline (2 weeks): 75mg amitriptyline and 3mg flupentixole; first treatment (5 weeks): 75mg amitriptyline and 3mg flupentixole (Scheme A) or 75mg amitriptyline alone (scheme B); washout period (2 weeks): both groups placebo; 2nd treatment (5 weeks) crossing over from Scheme A to B and vice versa.	Zung Depression Scale, Hamilton Depression Scale, clinical screening for extrapyramidal side effects, Abnormal Involuntary Movement Scale, pain intensities (numeric scale 0=no pain, 10=unbearable pain. No differences between the amitriptyline group and the amitriptyline+flupentixole group concerning the pain.	Type of pain: somatoform pain disorder; 2 refused to participate and 9 dropped out during treatment.
Langemark and Olesen, 199429	Randomized, double-blind, crossover, response-conditional pilot study	50 patients—mean age 42 years, recruited by mailed questionnaire. Inclusion criteria: chronic tension-type headache for at least 6 months and no more than 14 headache-free days per month.	Random assignment to either 20mg paroxetine or 400mg sulpiride (starting with 200mg for 1 week) daily for 8 weeks.	Headache diary beginning 4 weeks before treatment and during 8 weeks of treatment (5-point verbal scale (no/slight/moderate/very troublesome/worst possible headache) Change in headache score: drug given first: paroxetine (n=18)—0.4; sulpiride (n=19)—0.7.	Type of pain: chronic tension-type headache; 8 patients dropped out during treatment and 3 headache diaries were incomplete. One patient offered paroxetine first never took the drug. Depression was ruled out using the Bech-Rafaelsen Melancholia rating scale.
Graff-Radford et al., 200030	Double-blind, placebo-controlled, randomized trial	49 patients with mean age 72.9 years. Inclusion criteria: postherpetic neuralgia, pain duration equal to or longer than 6 months. Exclusion criteria: not stated.	Random assignment to 4 groups: Group 1: amitriptyline; Group 2: amitriptyline+fluphenazine; Group 3: fluphenazine; Group 4: placebo (active to mimic anticholinergic side effects). Starting dose: 12.5mg (amitriptyline) and 1mg (fluphenazine). Maximum doses: 200mg (amitriptyline) and 3mg (fluphenazine). 8 weeks, with 1 visit per week.	VAS, McGill Pain questionnaire, side effects scale, Minnesota Multiphasic Personality Inventory, Beck Depression Inventory, Spielberger State Trait Anxiety Inventory. VAS: significant changes in Groups 1 and 2, but none in Groups 3 or 4. Side effects: highest level in Group 3. No evident changes in psychometric measurements.	Type of pain: postherpetic neuralgia; 1 dropout owing to heavy sedation effect because of amitriptyline.
Honkaniemi et al., 200631	Double-blind, placebo-controlled, randomized trial	47 patients—41 females, 6 males; mean age: 36 years; mean duration of headache before admission: 75 hours. Inclusion criteria: diagnosis of migraine according to the diagnostic criteria of the International Headache Society (IHS). Exclusion criteria: long QT interval, usage of drugs prolonging QT interval, hepatic disease, epilepsy or history of seizures, hyperthyreosis, parkinsonism, chronic psychiatric disease, other neuroleptic medication, and intoxication.	Random assignment to either 5mg haloperidole in 500mL of normal saline or 500mL of normal saline alone as a 20- to 30-minute infusion.	Pain estimation by a VAS between 1 and 3 hours after the infusion. Marked or almost total pain relief.	Type of pain: acute migraine headache; 44 patients included in the placebo-controlled arm of the trial. Of these, 4 were rejected: 2 were included in the study twice, 1 did not fulfill the inclusion criteria and 1 was pain free before the infusion. Of the remaining 40, 36 were females and 4 males. The mean duration of the headache for these 40 patients was 67 hours. 80% of patients reported side effects, mainly motor agitation (53%) and sedation (53%).

VAS=visual analogue scale; p.o.=oral; i.v.=intravenous.

Eight of the 11 included studies had a parallel design, and three had a crossover design. Some trials had more than two arms and made more than one comparison.

Pain was patient-reported in all 11 trials. In one study, information on pain was provided by the patients' weekly ratings.²² In six trials, pain was reported using a pain diary.¹⁴, ²⁴, ²⁶, ²⁸, ²⁹, ³⁰ One trial documented the analgesic requirements of the patients on a numeric scale.²⁵ Two trials simply reported on the mere occurrence of pain.²³, ²⁷

All 11 included studies were conducted in a double-blind fashion. Eight trials compared an antipsychotic or a combination of analgesic/antipsychotic with placebo, and three studies compared an antipsychotic or a combination of analgesic/antipsychotic with an active compound (i.e., antidepressants, antiepileptics, or analgesics).

There were 1) four studies of tricyclic antipsychotics (flupentixole, fluphenazine, thioridazine, levomepromazine); 2) two studies of the butyrophenone haloperidole; and 3) five studies of benzamides (sulpiride, tiapride, pimozide) (Table 1).

Each of the following conditions was evaluated in one of the trials: somatoform pain disorder, postherpetic neuralgia, acute migraine headache, pain in terminal cancer, postoperative pain, trigeminal neuralgia, acute rheumatic pain, post-lumbar puncture headache, and acute myocardial infarction. In addition, chronic tension-type headache was evaluated in two studies.

Risk of Bias in Included Studies 

Each study was scored independently for quality by two of the review authors (M.A. and M.O.) using the three-item Jadad Quality Scale.¹⁹ The qualities of scores for individual trials are reported in the “Notes” column of Table 1. The median quality score for the placebo-controlled studies was 3 (all trials scored 3), and for the active control studies also, it was 3 (range: 3–4).

Effects of Interventions 

Four trials,²², ²³, ²⁸, ³⁰ with a total of 449 participants, studied the effects of tricyclic antipsychotics in different painful disorders. These trials studied the effect of tricyclic antipsychotics in pain after myocardial infarction,²³ pain because of terminal cancer,²² somatoform pain disorder,²⁸ and postherpetic neuralgia.³⁰ In the study by Johnston,²² thioridazine 75mg daily was not better than placebo with regard to global improvement and pain in terminal cancer patients (P<0.1).

Three studies compared tricyclic antipsychotics with other active treatments, including amitriptyline (a tricyclic antidepressant)²⁸, ³⁰ and meperidine (pethidine) (an opioid).²³ Administration of levomepromazine proved to reduce significantly the recurrence of pain within the first 72 hours after an acute myocardial infarction compared with treatment with meperidine (P<0.05).²³ In the case of postherpetic neuralgia, neither fluphenazine alone nor the combination of fluphenazine and amitriptyline significantly reduced pain.³⁰ In another study on somatoform pain disorder, treatment with the combination of 75mg amitriptyline and 3mg flupentixole was not superior to that with 75mg amitriptyline alone.²⁸

Two placebo-controlled RCTs,²⁵, ³¹ with a total of 81 participants, studied the effects of butyrophenones on postoperative pain²⁵ and acute migraine headache.³¹ In the case of postoperative pain, haloperidole (5 or 10mg orally) as premedication before major abdominal surgery was not superior to placebo.²⁵ Only a significant reduction of postoperative emesis was found in both groups treated with haloperidole. In contrast, treatment of acute migraine headache with 5 mg intravenous haloperidole was shown to be significantly superior to placebo (mean difference: −4.05 [95% confidence interval [CI]: −5.61 to −2.49]).³¹

Five double-blind trials, with a total of 240 participants, studied the effects of benzamides on different types of headaches,²⁴, ²⁷, ²⁹ trigeminal neuralgia,¹⁴ and acute rheumatic pain.²⁶ Two of these studies were placebo controlled.²⁴, ²⁷

The effect of intravenous tiapride (dose: 200mg) after lumbar puncture was studied in a small sample (n=30).²⁷ The authors only reported the percentage of patients who experienced pain within 48 hours after the procedure but did not provide any further details (e.g. pain severity or associated symptoms). When compared with the placebo, tiapride led to a significant reduction in the occurrence of headaches (P<0.01).

An Italian group reported on the efficacy of 300mg tiapride administered orally in chronic tension-type headache, but failed to provide any information on the duration of the treatment conducted in this study.²⁴ Forty percent of the patients treated with tiapride were complete responders compared with zero responders under placebo.²⁴

Sulpiride (400mg daily) and paroxetine, a selective serotonin-reuptake inhibitor (30mg daily), were compared in a group of 50 patients suffering from chronic tension-type headache in a crossover, conditional-response design.²⁹ Each treatment period lasted eight weeks. Patients recorded their pain in headache diaries. Total pain scores differed significantly between both groups (P=0.03), favoring treatment with the antipsychotic. It also seems noteworthy that five participants in the group receiving sulpiride dropped out during the study because of intolerable side effects.²⁹

Pimozide (12mg daily) and carbamazepine (1200mg daily), an antiepileptic drug, were tested in the treatment of pain caused by trigeminal neuralgia in 48 participants, using a crossover design.¹⁴ During both treatment phases, pimozide proved to be superior to carbamazepine regarding total trigeminal neuralgia pain scores (P<0.01; mean difference: −4.11 [95% CI: −8.08 to −0.14]).

In the case of acute rheumatic pain, tiapride (100mg daily) and glafenine, an anthranilic acid derivative with analgesic properties (200mg daily), were compared during a 14-day double-blind trial.²⁶ Tiapride was significantly superior to glafenine regarding the time delay until the disappearance of the pain (P<0.05) but failed to significantly reduce pain.²⁶

Fifty-four individuals were reported to be excluded or to have dropped out during the study in all 11 eligible RCTs.¹⁴, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹ Three studies did not report any dropouts.²⁵, ²⁶, ²⁷ In two studies, it was explicitly stated that no side effects had occurred during the intervention phase.²², ²⁴ One study did not report on side effects at all.²⁷ Of the remaining eight studies that reported side effects because of treatment with antipsychotics, three did not provide percentages or incidences of these side effects.²⁵, ²⁸, ³⁰

“Dry mouth” was the most commonly reported side effect, reported in five studies,²³, ²⁵, ²⁸, ²⁹, ³⁰ although side effects occurred in 34%–83% of study participants (Table 2). Harms were not evaluated with any kind of consistency or reliability, and much better evidence on harms is needed to reliably assess the balance of benefit to harm.

Table 2. Included Studies: Reported Side Effects

—=No information available.

Back to Article Outline

Discussion 

There are some preclinical studies in humans that link the dopaminergic system with pain. In one study, an inverse correlation of pain threshold and response criterion with the D₂/D₃ binding potential in the right putamen was found.³² This finding is supported by a number of animal studies, which have suggested that dopamine is involved in the regulation of nociception. However, the data are contradictory, as dopamine agonists have been shown to produce either antinociception³³ or hyperalgesia.³⁴

Although it appears reasonable to further investigate the analgesic effect of various antipsychotics in different pain syndromes, this systematic review revealed a small number (n=11) of small-sized clinical trials (total n=743) that compared the analgesic effects of antipsychotics with placebo or active compounds in a randomized, double-blind fashion.

In the case of headaches (i.e. migraine, tension-type headache), three studies showed significant pain reduction.²⁴, ²⁹, ³¹ Results regarding the treatment of neuropathic pain were contradictory. Treatment of postherpetic neuralgia with fluphenazine did not show a significant effect,³⁰ whereas pimozide led to a significant reduction of pain in trigeminal neuralgia.¹⁴

Only one additional study reported a statistically significant positive effect on pain, specifically pain after an acute myocardial infarction.²³ Trials on somatoform pain disorders,²⁸ postoperative pain,²⁵ and acute rheumatic pain²⁶ failed to deliver significant results favoring the treatment with antipsychotics.

Summarizing the results of all 11 included RCTs, we found a positive effect on painful conditions in six trials, whereas five trials failed to report any analgesic effect of the antipsychotics studied. The data have serious limitations: most trials only studied small samples of patients, and only one included more than 200 participants. Moreover, pain assessment varied among the different protocols. Some even only reported on the (re-)occurrence of pain, which is, from our point of view, not sufficient to assess the effect on painful states.

Further research on analgesic properties of antipsychotics in more RCTs is indicated. Atypical antipsychotics, which are known to produce fewer extrapyramidal side effects, are available, and this new group of antipsychotics clearly needs to be studied regarding its analgesic potency. So far, one study compared the analgesic effects of droperidole and olanzapine administered intramuscularly in a randomized, nonblinded study.³⁵ Both substances reduced the intensity of acute headache in more than 80% of study participants. Interestingly, the rates of akathasia were similar in both groups of patients.³⁵

Our search strategy yielded RCTs for antipsychotics that were not within the scope of this review (i.e., droperidol and prochlorperazine). After an amendment in our protocol, in the future, we plan to include these studies in an update of the present review on antipsychotics and pain.¹⁸

Back to Article Outline

Conclusions 

Because of limitations in the available evidence, further research is needed to understand whether antipsychotics are effective for acute or chronic pain or specific pain conditions.

Back to Article Outline

Acknowledgment 

The authors would like to thank Tiina Saarto for data extraction and translation of the manuscript.

Back to Article Outline

References 

1. Patt RB, Proper G, Reddy S. The neuroleptics as adjuvant analgesics. J Pain Symptom Manage. 1994;9:446–453
   • View In Article
   • MEDLINE
   • CrossRef
2. Burduk P, Guzik P, Piechocka M, et al. Comparison of fentanyl and droperidol mixture (neuroleptanalgesia II) with morphine on clinical outcomes in unstable angina patients. Cardiovasc Drugs Ther. 2000;14:259–269
   • View In Article
   • MEDLINE
   • CrossRef
3. Bloomfield S, Simard-Savoie S, Bernier J, Tetreault L. Comparative analgesic activity of levomepromazine and morphine in patients with chronic pain. Can Med Assoc J. 1964;90:1156–1159
   • View In Article
   • MEDLINE
4. Breitbart W. Psychotropic adjuvant analgesics for pain in cancer and AIDS. Psychooncology. 1998;7:333–345
   • View In Article
   • MEDLINE
   • CrossRef
5. Khojainova N, Santiago-Palma J, Kornick C, Breitbart W, Gonzales GR. Olanzapine in the management of cancer pain. J Pain Symptom Manage. 2002;23:346–350
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (58 KB)
   • CrossRef
6. Merskey H. Pharmacological approaches other than opioids in chronic non-cancer pain management. Acta Anaesthesiol Scand. 1997;41:187–190
   • View In Article
   • MEDLINE
   • CrossRef
7. Silberstein SD, Peres MF, Hopkins MM, et al. Olanzapine in the treatment of refractory migraine and chronic daily headache. Headache. 2002;42:515–518
   • View In Article
   • MEDLINE
   • CrossRef
8. Lu SR, Fuh JL, Juang KD, Wang SJ. Repetitive intravenous prochlorperazine treatment of patients with refractory chronic daily headache. Headache. 2000;40:724–729
   • View In Article
   • MEDLINE
   • CrossRef
9. Hakkarainen H, Allonen H. Ergotamine vs. metoclopramide vs. their combination in acute migraine attacks. Headache. 1982;22:10–12
   • View In Article
   • MEDLINE
   • CrossRef
10. Kiser RS, Cohen HM, Freedenfeld RN, Jewell C, Fuchs PN. Olanzapine for the treatment of fibromyalgia symptoms. J Pain Symptom Manage. 2001;22:704–708
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (45 KB)
    • CrossRef
11. Jermyn RT. A nonsurgical approach to low back pain. J Am Osteopath Assoc. 2001;101:S6–11
    • View In Article
    • MEDLINE
12. Feinberg SD. Prescribing analgesics. How to improve function and avoid toxicity when treating chronic pain. Geriatrics. 2000;55:44;49–50, 53
    • View In Article
    • MEDLINE
13. Gobel H, Stadler T. [Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine], Drugs. 1997;53(Suppl 2):34–39
    • View In Article
    • CrossRef
14. Lechin F, van der DB, Lechin ME, et al. Pimozide therapy for trigeminal neuralgia. Arch Neurol. 1989;46:960–963
    • View In Article
    • MEDLINE
15. Peschen-Rosin R. [Chronic facial pain from psychiatric point of view—differential diagnosis and therapeutic strategies], Schmerz. 2002;16:395–403
    • View In Article
    • MEDLINE
    • CrossRef
16. Gomez-Perez FJ, Rull JA, Dies H, et al. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind crossover study. Pain. 1985;23:395–400
    • View In Article
    • Abstract
    • Full-Text PDF (326 KB)
    • CrossRef
17. Nix WA. [What is certain in pain therapy? The analgesic potency of neuroleptics in the treatment of chronic pain. A metaanalysis], Schmerz. 1998;12:30–38
    • View In Article
    • MEDLINE
    • CrossRef
18. Seidel S, Aigner M, Ossege M, et al. Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2008;4:CD004844
    • View In Article
19. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;17:1–12
    • View In Article
    • Abstract
    • Full-Text PDF (891 KB)
    • CrossRef
20. Friedman BW, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med. 2008;52:399–406
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (821 KB)
    • CrossRef
21. Callan JE, Kostic MA, Bachrach EA, Rieg TS. Prochlorperazine vs. promethazine for headache treatment in the emergency department: a randomized controlled trial. J Emerg Med. 2008;35:247–253
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (141 KB)
    • CrossRef
22. Johnston B. Relief of mixed anxiety-depression in terminal cancer patients. Effect of thioridazine. N Y State J Med. 1972;72:2315–2317
    • View In Article
    • MEDLINE
23. Davidsen O, Lindeneg O, Walsh M. Analgesic treatment with levomepromazine in acute myocardial infarction. A randomized clinical trial. Acta Med Scand. 1979;205:191–194
    • View In Article
    • MEDLINE
    • CrossRef
24. Bussone G, Boiardi A, Merati B, et al. [Tiapride in the treatment of chronic headache], Riv Patol Nerv Ment. 1981;101:247–253(author's translation)
    • View In Article
    • MEDLINE
25. Judkins KC, Harmer M. Haloperidol as an adjunct analgesic in the management of postoperative pain. Anaesthesia. 1982;37:1118–1120
    • View In Article
    • MEDLINE
    • CrossRef
26. Ginsberg F, Bourguignon RP, Smets P, Famaey JP. Tiapride versus glafenine: a double-blind comparative study in the management of acute rheumatic pain. Curr Med Res Opin. 1983;8:562–569
    • View In Article
    • MEDLINE
    • CrossRef
27. Roux FX, Mallet A, Meresse S. [Prevention of headache following lumbar puncture. A controlled double blind trial of the effectiveness of intravenous tiapride], Sem Hop. 1983;59:319–321
    • View In Article
28. Zitman FG, Linssen AC, Edelbroek PM, Van Kempen GM. Does addition of low-dose flupentixol enhance the analgetic effects of low-dose amitriptyline in somatoform pain disorder?. Pain. 1991;47:25–30
    • View In Article
    • Abstract
    • Full-Text PDF (661 KB)
    • CrossRef
29. Langemark M, Olesen J. Sulpiride and paroxetine in the treatment of chronic tension-type headache. An explanatory double-blind trial. Headache. 1994;34:20–24
    • View In Article
    • MEDLINE
    • CrossRef
30. Graff-Radford SB, Shaw LR, Naliboff BN. Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Clin J Pain. 2000;16:188–192
    • View In Article
    • MEDLINE
    • CrossRef
31. Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006;46:781–787
    • View In Article
    • MEDLINE
    • CrossRef
32. Pertovaara A, Martikainen IK, Hagelberg N, et al. Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain. Eur J Neurosci. 2004;20:1587–1592
    • View In Article
    • MEDLINE
    • CrossRef
33. Shimizu T, Iwata S, Morioka H, et al. Antinociceptive mechanism of L-DOPA. Pain. 2004;110:246–249
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (124 KB)
    • CrossRef
34. Paalzow GH. L-dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses. J Pharmacol Exp Ther. 1992;263:470–479
    • View In Article
    • MEDLINE
35. Hill CH, Miner JR, Martel ML. Olanzapine versus droperidol for the treatment of primary headache in the emergency department. Acad Emerg Med. 2008;15(9):806–811
    • View In Article
    • CrossRef