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13 Articles in Volume 18, Issue #6
Advice for the Advanced Practice Provider
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
Considering Comorbidities When Selecting Medications (Part 2)
Gaps in the Pharmacist’s Pain Management Role
How can cyproheptadine manage complicated chronic pain cases?
Letters to the Editor: Trackable Pills; Buprenorphine; CRPS Diagnosis
Managing Opioid Use Disorder
Mobile Trackers and Digital Therapeutics
New Insights in Understanding Chronic, Central Pain
Nocebo Effects: How to Prevent them in Patients
Polarizing Topics in Chronic Pain
The Fight to End Peripheral Neuropathy
Urine Drug Monitoring

How can cyproheptadine manage complicated chronic pain cases?

Tips for using the antihistamine to treat sleep disorders, sexual dysfunction, refractory headaches, and more.
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Clinicians managing chronic pain are often confronted with other medical problems and complications that typically accompany chronic pain diseases. Common comorbid pain enhancers may include poor sleep, changes in appetite, and elevated stress, as well as anxiety, depression, and other mood changes.1 Pain precipitates these complications, which then exacerbate pain experiences that feed into a vicious cycle. For instance, the frequency and severity of insomnia has been directly correlated to pain sensitivity.2 To successfully manage chronic pain, attention therefore must be given to these other factors to improve the patient’s overall function and quality of life.

About Cyproheptadine

Cyproheptadine, an antihistamine, was initially approved in 1961 for allergic conditions but its use has been expanded to include treatment of serotonin syndrome, serotonin-induced sexual dysfunction, insomnia, headaches, and for use as an appetite stimulant. See Figure 1 for a representation of the chemical structure. Here, the authors review the potential application of cyproheptadine in the treatment of chronic pain, including its mechanism of action, supporting evidence, implications, and limitations.

Cyproheptadine is a first-generation antihistamine of the piperidine class with additional anticholinergic, antiserotonergic, and local anesthetic properties.3 Cyproheptadine functions as a potent antagonist at the histamine-1 (H1) receptor, and inhibits muscarinic receptors and serotonin 5-HT2 and 5-HT1 receptors at higher doses. Binding affinities for various receptors are presented in Table I along with affinities for amitriptyline, a tricyclic antidepressant, as a reference.4

Role in Managing Antidepressant-Induced Sexual Dysfunction

Antidepressant classes, serotonin-norepinephrine reuptake inhibitors (SNRI), and tricyclic antidepressants (TCA) are commonly used in treatment of neuropathic and other pain syndromes. However, sexual dysfunction is a common side effect that occurs to some degree in 30 to 40% of patients taking antidepressants that inhibit the reuptake of serotonin.5 Antidepressants may have an adverse impact on all phases of healthy sexual function including libido, arousal, and orgasm.

An inability to experience full sexual pleasure is frequently problematic for chronic pain patients because the activity alone can be too painful, but several drug classes commonly prescribed to treat chronic pain may also be a contributory factor in reduced sexual arousal. This may create a dilemma for the patient who is taking an antidepressant for pain management, depression or both, despite potential efficacy. Antidepressant-related sexual dysfunction appears related to increased serotonergic activity, particularly at the 5HT2 and 5HT3 receptors.

Cyproheptadine’s inhibition of 5HT2 receptors is thought to attenuate antidepressant-induced sexual dysfunction. In a case series of seven patients with antidepressant-induced sexual dysfunction, cyproheptadine (4 to 12 mg) was administered 1 to 2 hours prior to sexual intercourse.6 Five of the patients reported improved sexual function, particularly in libido and orgasm, although the beneficial effect was transient in two of these individuals. Of note, all patients exhibited sedation the next day. These results suggest that cyproheptadine used as needed may attenuate serotonin in some patients. Regardless, sedation should be discussed as this may hinder sexual performance as well as next day functioning. For a patient who is already on cyproheptadine and who demonstrates a tolerance to the sedation, taking an as-needed dose prior to sexual intercourse may be a reasonable accommodation.

However, for the vast majority of patients faced with antidepressant-induced sexual dysfunction, clinicians are best advised to avoid prescribing agents with post-synaptic serotonergic activity.7 Useful options may include bupropion and mirtazapine.

Bupropion is an FDA-approved dopamine and norepinephrine reuptake inhibitor indicated to treat depression. This medication also has demonstrated efficacy in neuropathic pain.8,9 Its dopamine effects may help to improve libido.10,11

Mirtazapine, an oral medication indicated for treating depression, works by blocking presynaptic alpha-2-adenergic receptors and post-synaptic 5-HT2 and 5-HT3 receptors, the latter of which is thought to contribute to lower incidence of sexual dysfunction.7,12 Data supports mirtazapine’s efficacy in the treatment of pain specifically associated with post-herpetic neuralgia.13 Additionally, mirtazapine has been shown to induce minimal sexual disruption when compared to atypical antidepressants.

Other therapeutic treatments that do not lead to antidepressant-induced sexual dysfunction include buspirone, trazodone, and nefazodone.7 Trazodone and nefazodone are serotonin antagonists and reuptake inhibitors (SARI). Their antagonism of the 5HT2A receptor is thought to result in less interference with sexual pleasure.

Role as a Sleep-Inducing Agent

Cyproheptadine’s presumed efficacy in sleep is likely due to its anticholinergic activity. Cyproheptadine is a first-generation antihistamine similar to diphenhydramine with the ability to penetrate the blood-brain barrier, and therefore, imposing a sedative effect.3 There are no published studies evaluating cyproheptadine in insomnia; however, efficacy is inferred from studies evaluating diphenhydramine.14 Anti-histamines have been shown to affect both sleep latency and maintenance.14,15 Anti-histamines may be effective as short-term or temporary treatment of insomnia, for no more than 2 to 3 nights, but these agents are not effective in addressing chronic insomnia.15 This limited value is likely due to tachyphylaxis, where tolerance to the sedative effect builds with continued use. Tachyphylaxis to anti-histamines has been reported as early as in 3 days. However, some studies demonstrate efficacy for up to 2 weeks, although the hypnotic effect appears to decrease over time.14

Last updated on: September 5, 2018
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