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13 Articles in Volume 18, Issue #6
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
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 a New High-Dose Opioid Patient
Managing Opioid Use Disorder
Medication Selection for Comorbid Pain Management (Part 2)
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.

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

Role in Refractory Headaches

Some headaches originate due to activation of the trigeminal system when serotonin is released from platelets, exerting a vasocontractile effect that decreases blood flow to the cerebrum.16,17 This decrease in serotonin causes vasodilation in the cerebrum in addition to stimulation of the trigeminal nerve. When vasoactive peptides are released within this system, the result is to induce an inflammatory response.18,19

There are seven types of serotonin receptors, however, only the 5HT1 and 5HT2 receptors are known to play a direct role in causing a vasoconstriction of the cerebrum. The 5HT1 receptor is located primarily in blood vessels of the cerebrum. Additionally, the 5HT1B and 5HT1D subunits are also believed to be involved in the vasoconstriction in the cerebrum, resulting in migraines. With regard to 5HT1D, it has been shown to inhibit the release of vasoactive peptides at terminals of trigeminal nerves.20 Hence, the prophylaxis of headaches when cyproheptadine is introduced is thought to arise from its inhibitory effects on peptide release, inhibiting 5HT1B and 5HT1D and preventing an inflammatory response caused by trigeminal nerve stimulation.21

An open-label study was conducted in 12 patients with migraines refractory to lomerizine, topiramate, or valproic acid therapy.22 Each patient received cyproheptadine (4 mg) at bedtime and those patients who did not experience clinically excessive drowsiness received an additional dose of the medication with breakfast. A reduction in migraine frequency was reported in all subjects within 7 to 10 days of treatment initiation. Migraine frequency decreased from 10 or more episodes to 2.6 events per month (P = 0.01).22

In a randomized, placebo-controlled trial involving 259 patients given cyproheptadine (2 mg twice a day), propranolol (40 mg twice a day), both, or placebo, the researchers reported statistically and clinically significant reductions in migraine frequency, duration, and severity in all treated groups during a three-month followup, except in those receiving the placebo.23 The groups treated with an individual drug had higher dropout rates (propranolol 11%; cyproheptadine 16%) than the group given the combination treatment (7%).

As such, cyproheptadine may be a viable therapeutic option for patients who have not experienced relief with drugs currently used for migraine prevention, such as beta blockers and antiepileptics. While cyproheptadine may improve symptoms in patients who experience refractory headaches, this medication is not intended for extended use. And, it should be noted that the anti-serotoninergic effects of cyproheptadine may result in confusion and visual hallucinations at high doses. Another important adverse effect is weight gain, a problem that is addressed in the next section.

Role as an Appetite Stimulant

Appetite stimulants have been used to help pediatric, adult, and geriatric patients who struggle with decreased appetite, anorexia, and cachexia that may stem from chronic diseases like cystic fibrosis, cancer, and HIV/AIDS. Megestrol, cyproheptadine, anabolic steroids, growth hormones, and cannabinoids have all been used for their appetite-stimulating properties. Most of these appetite stimulants produce negative side effects, making them unfavorable therapeutic choices for long-term use.24

The inhibitory effect that cyproheptadine has on serotonin receptors in the hypothalamus likely accounts for its ability to stimulate appetite.3,24-27 In a randomized, placebo-controlled, 12-week trial of pediatric patients with cystic fibrosis, cyproheptadine (2 to 4 mg four times daily) resulted in a mean weight gain of 3.45 kg compared to 1.1 kg in patients receiving the placebo.25

Twelve of these patients participated in an additional nine-month followup study to assess long-term effects.24,25 Patients from the placebo arm received cyproheptadine (4 mg up to four times daily) and showed a mean weight gain of 3.87 kg. Patients from the cyproheptadine arm continued cyproheptadine and maintained previously gained weight and had an additional 0.87 kg weight gain. Patients who continued the cyproheptadine treatment retained the weight gained over the course of the study; otherwise, side effects were reported as mild. Using results from both the short and long-term studies, cyproheptadine appears effective as an appetite stimulant for patients with cystic fibrosis, supporting a desirable weight gain with minimal adverse side effects.24,25

In contrast to pediatric studies, the trials conducted with adult patients yielded conflicting results. Findings from a randomized placebo-controlled study by Noble26 and a cross-over study by Silverstone, et al,27 demonstrated increase in appetite and body weight with cyproheptadine in adults.26 However, in a randomized placebo-controlled trial of patients with advanced cancer cyproheptadine (8 mg three times daily) resulted in a mean decrease in weight of 2.0 kg/month as compared to a mean decrease of 2.2 kg/month in patients receiving placebo, although this finding was not significant (P = 0.72). Patients assigned to cyproheptadine reported less nausea (P = 0.02), more sedation (P = 0.07), and more dizziness (P = 0.01) than patients on placebo.28

Overall Use of Cyproheptadine in Pain Management

Overall, adverse drug reactions common in patients taking cyproheptadine may be predicted based on its mechanism of action and target receptors. Adverse events related to antihistaminergic and anticholinergic activity have been reported, including sedation, blurred vision, dry mouth, dry eyes, constipation, urinary retention, and confusion. Therefore, cyproheptadine is not recommended in patients with glaucoma since its anticholinergic effects may lead to increased intraocular pressure. Additionally, cyproheptadine may worsen urinary retention in patients with benign prostate hyperplasia. Another group of patients who should be precluded from cyproheptadine treatment are those taking an opioid since the combination may enhance sedation and induce constipation.

Although not a first-line pain therapeutic, cyproheptadine may represent a pain management option for refractory headaches and relief of symptoms acerbated by chronic pain such as insomnia and cachexia. Cyproheptadine may also be efficacious in patients who suffer from comorbid chronic pain and sleep disorders, headache, and/or decreased appetite.

The medication may also be useful for iatrogenic sleep disorders in patients with a chronic pain syndrome. Consideration of its application in clinical practice will likely depend upon the patient who has exhausted first-line agents for the given indication. It also may be a reasonable option for patients with more than one of the favorable indications (eg, having poor appetite along with antidepressant-induced sexual dysfunction).

Last updated on: September 5, 2018
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