Atypical Antipsychotics as Adjuncts in Chronic Pain Management: How Effective Are They?

Chronic pain is a significant source of disability, affecting more than 10% of the US population.¹ Opioid therapy is commonly the first line of treatment for chronic pain; however, long-term opioid use carries the risk for significant side effects, dependency, and abuse.²

Atypical antipsychotics (AAs), often referred to as second-generation antipsychotics, are used to treat psychotic and mood disorders such as schizophrenia, bipolar disorder, and depression.³

These medications are characterized by effectiveness that is comparable to first-generation antipsychotic medications⁴ and a lower incidence of certain side effects, such as extrapyramidal symptoms and tardive dyskinesia.³  

In recent years, AAs — particularly olanzapine and quetiapine — have gained increasing attention as adjuncts in pain management regimens.² Several studies reported a significant improvement in the control of pain and symptoms associated with fibromyalgia with olanzapine treatment,^5,6 and quetiapine was found to be effective for migraine in an open pilot study.⁷ Although early studies show promising results, medical consensus and guidance on the use of AAs in chronic pain management is still lacking. In this context, therapeutic decisions are based on a careful consideration of the potential risks vs benefits associated with these drugs.⁸

In an interview with Clinical Pain Advisor, Xavier Jimenez, MD, medical director of the Chronic Pain Rehabilitation Program at Cleveland Clinic in Ohio and Hani R. Khouzam, MD, MPH, staff psychiatrist at the General Mental Health Clinic, Veterans Affairs, Central California Health Care System in Fresno, discussed the latest insights on the use of AAs in chronic pain management.

Clinical Pain Advisor: What is the clinical evidence supporting the use of AAs in pain management?

Dr Xavier Jimenez: At this time, there is significant evidence to suggest the role of AAs in certain areas of chronic pain management. A very recent systematic review performed by our team reveals that at least 20 studies examined 5 different AAs in a variety of chronic pain syndromes.² The studies included retrospective analyses, randomized controlled trials, and smaller case series, and their methods and results varied. However, we concluded that at least one AA (olanzapine) demonstrates higher evidence of efficacy in certain chronic pain syndromes, particularly those featuring central sensitization and/or psychiatric comorbidity. Given the high prevalence of such chronic pain [in patients] in the health care system, it is likely that olanzapine, and possibly other AAs, will become increasingly common in future chronic pain management.  

Clinical Pain Advisor: Which AAs have been studied the most for pain control? Are certain AAs more effective than others in controlling pain?

Dr Jimenez: As evidenced by our review,² olanzapine has been studied the most of all AAs (11 total studies). Given the quality and quantity of studies, olanzapine is the AA with the highest efficacy in chronic pain syndromes, particularly fibromyalgia, headache/migraine, and possibly other central sensitization syndromes. With 6 published studies, quetiapine is the second most studied and efficacious of the AAs, and it is used mostly in headache/migraine. 

Clinical Pain Advisor: What are the mechanisms underlying the effectiveness of AAs in managing pain?

Dr Jimenez: AAs likely contribute to chronic pain management by multiple mechanisms. Their receptor heterogeneity — action on dopaminergic, histaminic, adrenergic, serotonergic, and still other receptors — is similar to that of tricyclic antidepressants, which are known to be effective in chronic pain management. AAs likely help reduce central sensitization as well, particularly in brain-based pain processing areas such as paralimbic structures. Finally, AAs are efficacious in treating psychiatric comorbidities (mood disorders, anxiety disorders, etc), which often accompany chronic pain conditions. AAs may thus help indirectly with control of such conditions, thereby lessening the overall pain symptom experience. 

Clinical Pain Advisor: What are some of the advantages of using AAs in pain management?

Dr Jimenez: Advantages to the use of AAs may be numerous. They include lack of physiologic dependence and/or addiction, which is a serious concern when compared with traditional, yet problematic alternatives such as opioids. As such, AAs are not controlled substances and do not require close monitoring from any legalistic standpoint. Pharmacologically, AAs may also act rapidly; they do not require weeks of treatment to take effect, as is the case with various tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (eg, duloxetine). Finally, AAs may also have double action in terms of both chronic pain and psychiatric symptom control. Of course, these benefits must be weighed against the disadvantages and side effects associated with AAs, which may include weight gain, metabolic changes, neurologic effects, and cardiac risk. These are reviewed closely in our published study and clinical guidance is offered on how to calculate both benefits and risks associated with judicious AA use in certain chronic pain conditions.² 

Clinical Pain Advisor: Which patients with chronic pain are best suited to receive AAs as part of their pain management program?

Dr Khouzam: Patients with co-occurring psychotic symptoms and those who are not at risk for weight gain or type 2 diabetes are good candidates for treatment with AAs.

Clinical Pain Advisor: Which considerations should be taken into account when prescribing AAs for pain management?

Dr Khouzam: The age of the patient and the presence of any comorbid conditions should be considered when prescribing AAs. Clinicians should avoid prescribing AAs in the elderly and in overweight patients. Ongoing monitoring for possible development of metabolic syndrome should also be implemented in patients treated with AAs.

Clinical Pain Advisor: What types of studies still need to be performed to further evaluate the use of AAs in pain management?

Dr Khouzam: Randomized double-blind placebo-controlled studies with a larger population size that include standardized pain assessment would be the preferred studies to conduct to confirm the existing anecdotal findings for using AAs as adjunctive agents for the treatment of chronic pain. In addition to fibromyalgia, other chronic pain conditions for which the use of AAs could be investigated include migraine headaches, facial pain, diabetic neuropathy, musculoskeletal pain, postherpetic neuralgia, and pain associated with cancer and AIDS.⁸ Furthermore, to the best of my knowledge, the AAs asenapine, iloperidone, lurasidone, or paliperidone have not yet been investigated in clinical trials as adjunctive treatment in patients with chronic pain conditions.

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References

1. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015;16(8):769-780.
2. Jimenez XF, Sundararajan T, Covington EC. A systematic review of atypical antipsychotics in chronic pain management: Olanzapine demonstrates potential in central sensitization, fibromyalgia, and headache/migraine [published online October 26, 2017]. Clin J Pain. doi:10.1097/AJP.0000000000000567
3. Mauri MC, Paletta S, Maffini M, et al. Clinical pharmacology of atypical antipsychotics: an update. EXCLI J. 2014;13:1163-1191.
4. Seidel S, Aigner M, Ossege M, et al. Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2013;(8):CD004844.
5. Freedenfeld RN, Murray M, Fuchs PN, Kiser RS. Decreased pain and improved quality of life in fibromyalgia patients treated with olanzapine, an atypical neuroleptic. Pain Pract. 2006;6(2):112-118.
6. Kiser RS, Cohen HM, Freedenfeld RN, Jewell C, Fuchs PN. Olanzapine for the treatment of fibromyalgia symptoms. J Pain Symptom Manage. 2001;22(2):704-708.
7. Krymchantowski AV, Jevoux C. Quetiapine for the prevention of migraine refractory to the combination of atenolol + nortriptyline + flunarizine. Arq Neuropsiquiatr. 2008;66(3B):615-618.
8. Khouzam HR. Psychopharmacology of chronic pain: a focus on antidepressants and atypical antipsychotics. Postgrad Med. 2016;128(3):323-330.