SEX, [pain] DRUGS, and ROCK & ROLL

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Although a focus of pain management is to improve functionality and quality of life, and choice of regimens can be “gray”, side effects from medications are more predictably printed in black and white.  The discussion of sexual dysfunction associated with medications used for pain management is often cast aside because of discussion comfort levels among patients and clinicians.  It is however an important topic.  As promised, this is Part 2 of our original post, Chronic Pain, Sex, Passion, and Shades of Grey.

Below, three guest bloggers, Drs. Alexandra H. Kawola and Thien C. Pham, PGY1 General Practice and PGY2 Pharmacy Pain Residents respectively, and Ms. Erika F. Prouty, Pharm.D. Candidate, 2015 delineate various pain medication classes commonly used that are attributable to sexual dysfunction and loss of libido. This post also suggests certain ways to overcome these pharmacological obstacles.  Included in their discussion are antidepressants, anticonvulsants and opioids.

Antidepressants

Antidepressant use has become a mainstay for treatment for neuropathic, and more recently even generalized pain. Sexual side effects have emerged as a growing concern among patients prescribed antidepressants. The incidence of sexual side effect, however, is difficult to estimate because the cause of sexual dysfunction can be associated with the disease state, interpersonal difficulties and medications. Few quality studies have focused on the nature of antidepressant associated sexual dysfunction, however there are some proposed mechanisms and remedies. Understanding the reason behind dysfunction is important as decreased libido, erectile dysfunction and delayed or absent orgasm may lead to poor adherence and ultimately poor therapy outcomes.

Multiple pharmacological mechanisms have been proposed and are neurotransmitter-specific based. Serotonin, norepinephrine, dopamine, prolactin and nitric oxide are all substances that have been studied as probable causes for sexual dysfunction due to antidepressant use.

The following are proposed ways to manage sexual dysfunction.

1. Wait for drug tolerance to develop
2. Dose reduction
3. Switch antidepressants  – Lowest rates of sexual side effects include nefazodone, bupropion and mirtazapine
4. Augmentation drug-induced sexual dysfunction with an “antidote”

It is important for patients to be reassured that sexual dysfunction is generally reversible when the medication is discontinued.  One strategy for dysfunction is to wait for tolerance to develop or lowering the dose, however symptoms do not always resolve. For this reason, this article will explain how to select antidepressants that are less likely to cause sexual dysfunction, or augment therapy if switching is not a therapeutic option.

Serotonin

Evidence linking serotonin to sexual response is difficult because there are no agents which are exclusively selective to serotonin. Animal studies, however, have demonstrated there are different roles between different serotonin receptors. It has been proposed that 5-HT_1a receptors facilitate sexual behaviors, whereas 5-HT_2c/1b inhibits sexual behaviors. Based on this mechanism, one proposed regimen to combat sexual dysfunction is to augment therapy with an antidote.

1. Anti-serotonergic Drugs: Antidotes that have been studied, express 5-HT₂ antagonistic effects such as the antihistamine, cyproheptadine. Cyproheptadine has been given to patients on “as needed”, or perhaps better phrased “as desired” basis and also by regularly scheduled dosing. Case reports attest to its efficacy, specifically with anorgasmia (lack or orgasm), however concern has been raised that therapeutic effects of the antidepressant may be diminished. Additionally, use of cyproheptadine is often limited due to excessive sedation.

Dopamine

Dopamine neurotransmission has been directly associated with sexual arousal. This has been evident by increased libido in patients receiving L-dopa for Parkinson’s Disease. Commonly used antidepressants regulate dopamine to different effects which offers an explanation as to why some antidepressants cause more sexual dysfunction than others.Switch to a different antidepressant: Paroxetine has a strong affinity for serotonin receptors and very limited effect on dopamine. Several other specific serotonin reuptake inhibitors (SSRIs) cause small amounts of dopamine reuptake inhibition. This elevation of dopamine can lead to increased sexual arousal. For this reason, consider avoiding use of paroxetine in patients affected by or concerned with sexual dysfunction.

1. Switch to a different antidepressant: Paroxetine has a strong affinity for serotonin receptors and very limited effect on dopamine. Several other specific serotonin reuptake inhibitors (SSRIs) cause small amounts of dopamine reuptake inhibition. This elevation of dopamine can lead to increased sexual arousal. For this reason, consider avoiding use of paroxetine in patients affected by or concerned with sexual dysfunction.
2. Switch or augment therapy: Bupropion is an atypical antidepressant that has been associated with improvement in sexual function. Bupropion has dopamine reuptake inhibition properties which could explain the lack of sexual dysfunction and perhaps enhanced function. Combination use of bupropion with an SSRI is common and often well tolerated, however incidence of adverse reactions and drug interactions should be considered.
3. Augment therapy: Addition of dopamine agonist, including dextromethorphan, low dose dextroamphetamine and amantadine have also been studied to decrease sexual dysfunction associated with antidepressants. Addition of these agents have demonstrated a diminished orgasm threshold and enhanced libido.

Prolactin

Increased serotonin and decreased dopamine have been noted to increase prolactin release from the hypothalamus. Elevated prolactin levels have been associated with diminished sexual desire and performance. Antidepressants with strong serotonergic activity and low dopaminergic activity can cause elevated prolactin levels, increasing risk for sexually related side effects.

1. Switch or augment: In order to decrease risk of sexual side effects, it is recommended to avoid antidepressants with strong serotonergic activity that is devoid of dopamine reuptake inhibition. Alternatively, as stated above, elevated prolactin could be combated through use of dopaminergic agents, such as bupropion.

Treatment of sexual dysfunction associated with antidepressants is an important issue but still lacks strong evidence. In order to increase quality of life and adherence in these patients, sexual side effects should be assessed and addressed.

Anticonvulsants

There has long been evidence associating anticonvulsant agents and sexual dysfunction in both men and women.  Most documentation has been reported in patients with epilepsy, a population who are likely the commonest users of these agents to control their disorder.  However, anticonvulsants are also frequently used in patients suffering from chronic neuropathic pain since they exhibit pain relief properties by varying pharmacological mechanisms.  Although it is not known exactly how these agents help reduce neuropathic pain, it is suggested they do so mainly by blocking pain signals from the body’s central nervous system.  Most studies relating anti-convulsants with sexual dysfunction are with the older agents, such as phenytoin, phenobarbital, carbamazepine, and valproic acid.  These agents have been shown to decrease libido, caase anorgasmia, and a decrease in testosterone levels (testosterone is linked to sexual drive in both men and women).  They even have been associated with sperm abnormalities in men.  These agents are also what are known as ‘hepatic-enzyme inducers’ through Phase I (CYP 450) metabolism, which stimulates the production of sex-hormone binding globulin (SHBG), a glycoprotein that binds to sex hormones and inhibits their ability to function.   An increase in SHBG therefore decreases the amount of free testosterone, a side effect of these older agents.

So what options are available for those patients concerned with these side effects?  Newer agents, such as lamotrigine, gabapentin, pregabalin, and levetiracetam do not undergo Phase I metabolism.  These agents have had little to no association with the sexual dysfunction side effects as compared to the older agents. In fact, there have been some reports of priapism from both gabapentin and pregabalin, so caustion needs to be exhibited here, as this is considered a medical emergency.  For patients who require continued use of anticonvulsant agents for neuropathic pain, the newer agents could serve as appropriate alternatives and patients may opt to speak with their providers if sexual dysfunction is a concern.

Opioids

Chronic use of opioids and their effects on the hypothalamic-pituitary-gonadal axis (HPGA) and endocrine function has been well established and published over the years.  Some specific symptoms from these hormonal effects consist of decreased libido and activity, erectile dysfunction, small or shrinking testes, decreased sperm count (leading to possible infertility), and hot flashes. Other less specific symptoms include decreased energy/motivation/initiative/self-confidence, depressed mood, poor concentration and memory, and diminished physical performance. As a result of these hormonal side effects from long-term opioid therapy, quality of life may be diminished for a patient living with a chronic pain syndrome.

As outlined in a previous PainDr.com blog, Opioid-Induced Androgen Deficiency (OPIAD), the HPGA is a sophisticated biochemical system that regulates the release of sex hormones through an endogenous negative feedback mechanism originating from the hypothalamus.  Figure 1 illustrates the effects of opioids on the HPGA inhibiting the release of gonadotropin-hormone releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating hormone (FSH),plus testosterone and estrogen.  The management OPIAD may include:

1. Discontinuation of opioid therapy
2. Reducing the opioid dose
3. Opioid rotation
4. Hormone replacement therapy

Figure 1:  Effects of opioids on the endocrine system

Male patients who complain of pain to the point where it is debilitating and are “unable to function”, often are co-prescribed sildenafil citrate (Viagara®).  It also is important to obtain testosterone levels and replace if necessary, because low testosterone also places male patients at risk of osteoporosis which generally is not tested routinely in males.  But, resultant decreased bone density in this population because of low “T” presents the inherent risk of bone fractures.  Considering that one may be using chronic opioid therapy for failed back syndrome, spinal fractures could be extremely debilitating.

So there you have it.  At least three major drug classes commonly used to treat various pain syndromes can clearly affect sexual function.  This coupled with pain itself, exhaustion, and mood can all have a negative impact a patient’s well-being, self-worth, and overall life pleasure.  It is for all of these reasons that we encourage first and foremost, an educated clinician and patient.  Also, patients with chronic pain should consider healthy life style choices, exercise, alternative medications if appropriate, couples counseling, and most of all a positive outlook and hope.

As always, comments and discussions are enthusiastically welcomed.

Our Guest Authors

Alexandra Hubbard Kawola, Pharm.D.  better known as Ali, is a PGY-1 Pharmacy Resident at the Stratton VA Medical Center in Albany, NY. She completed her Doctor of Pharmacy degree at Albany College of Pharmacy and Health Sciences in Albany, NY.  She has taken an interest in ambulatory care pharmacy and hopes to become a board-certified ambulatory care pharmacist. 

Thien Cong Pham, B.S., Pharm.D. is a PGY2 Pain & Palliative Care Pharmacy Resident at the Stratton VA Medical Center in Albany, NY.  A Navy Veteran, Dr. Pham completed a PGY1 Pharmacy Practice Residency at Veterans Affairs Medical Center in Palo Alto, CA.  Prior to receiving his Doctor of Pharmacy at Touro University California in Vallejo, CA, he received his Bachelors Degree in Biochemistry with a Medical Sciences emphasis from the University of California Riverside and Associate of Science from Riverside City College in Riverside, CA.

Erika Prouty, BS Bio, BS Environmental Sci. is a Student Pharmacist studying with the Western New England University, College of Pharmacy, Class of 2015. She is currently part of the Mini-Residency program at the Stratton VA Medical Center in Albany, NY; a program designed to mimic the longitudinal and clinical aspects anticipated as a PGY1 Pharmacy Resident. In 2011, she received her Bachelors in Biology and Bachelors of Environmental Science from Westfield State University. In 2008, she received her Associates in Liberal Arts and General Studies from Springfield Technical Community College. Erika likes walks on the beach and traveling to other countries.

The content herein is the opinion of the authors and was not prepared as part of their government duties, nor was this reviewed or approved by any government agency.

REFERENCES:

1. Zajecka J, Fawcett J, Schaff M, et al: The Role of Serotonin in Sexual Dysfunction: Fluoxetine-associated orgasm dysfunction, J Clin Psychiatry 52: 163-164, 1991.
2. Prabhakar, D, Balon R. How do SSRIs cause Sexual Dysfunction? Current Psych. 9(12);30-34, 2010.
3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999 Feb;19(1):67-85.
4. Harden, Cynthia L., MD. Sexualiy in Men and Women With Epilepsy. CNS Spectr. 2006; 11:8 (Suppl 9): 13-18.
5. Macphee GJA, Larkin JG, Butler E, Beastall GH, Brodie MJ. Circulating Hormones and Pituitary Responsiveness in Young Epileptic Men Receiving Long-Term Antiepileptic Medication. Epilepsia. 1988. 29 (4): 468-475.
6. Herzog AG, Drislane FW, Schomer DL, et al. Differential Effects of Antiepileptic Drugs on Sexual Function and Reproductive Hormones in Men with Epilepsy: Interim Analysis of a Comparison between Lamotrigine and Enzyme-Inducing Antiepileptic Drugs. Epilepsia. 2004. 45 (7): 764-768.
7. Lossius MI, Tauboll E, Mowinckel P, et al. Reversible Effects of Antiepileptic Drugs on Reproductive Endocrine Function in Men and Women with Epilepsy- A Prospective Randomized Double-Blind Withdrawal Study. Epilepsia. 2007. 48 (10): 1875-1882.

1. Bhasin S1, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59.
2. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002 Oct;3(5):377-84.
3. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009 Feb;25(2):170-5.
4. Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012 Jul;15(3 Suppl):ES145-56.
5. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013 Mar;126(3 Suppl 1):S12-8.
6. Paredes RG. Opioids and sexual reward. Pharmacol Biochem Behav. 2014 Jun;121:124-31.
7. World Health Organization. Patterns and consequences of the use of amphetamine-type stimulants (ATS). Technical Briefs on amphetamine-type stimulants (ATS).  Available at: http://www.who.int/hiv/pub/idu/ats_tech_brief/en/