Peter Huynh, Joseph Villaluz, Harjot Bhandal, Navid Alem, Rakhi Dayal, Long-Term Opioid Therapy: The Burden of Adverse Effects, Pain Medicine, Volume 22, Issue 9, September 2021, Pages 2128–2130, https://doi.org/10.1093/pm/pnab071
Navbar Search Filter Mobile Enter search term Search Navbar Search Filter Enter search term SearchSince introducing “pain as a fifth vital sign” campaign, the utilization of opioids to treat chronic noncancer pain has dramatically increased [ 1]. Chronic opioid therapy may be associated with varied deleterious effects including constipation, central sleep apnea, hypogonadism, hyperalgesia, adrenal insufficiency, osteoporosis, and tremors [ 2, 3]. Gomez et al. demonstrated that less than 20 morphine milligram equivalents (MME) per day did not increase morbidity and mortality, whereas threefold increase in morbidity and mortality was noted at doses over 200 MME per day [ 4]. Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids in chronic pain recommend using risk mitigation strategies when increasing opioid dosing to >50 MME/day and avoiding or carefully justifying increases to >90 MME/day [ 5].Our case highlights the possible extreme adverse effects and healthcare burden of long-term high dose opioid medication use.
A 57-year-old man status post L5-S1 fusion presented with chronic nonradicular low back pain since 1984. Previous treatments included interventional pain procedures, topical patches, and acupuncture without relief. Opioid treatment initiated in 1995 was continued ever since and gradually escalated. The patient reported significant analgesia and improved functional activities but subsequently developed adverse effects from the treatment. In 1999, he experienced severe worsening of existing constipation followed with severe gastroesophageal reflux disease (GERD). At the age of 41, he required a colonoscopy for manual fecal disimpaction and an esophagogastroduodenoscopy for gastric dysmotility workup. In 2003, he developed urinary stasis and ureteral calculi attributed to dysfunctional voiding secondary to opioid use or chronic constipation, or a combination of both. He underwent multiple imaging studies and urological procedures for calculi removal and bilateral ureteral stent placement. For atypical chest pain, he underwent evaluation by cardiology. Etiology possibly associated with underlying GERD. Complaining of daytime tiredness in 2007, he developed severe obstructive apnea with an apnea-hypopnea index (AHI) of 69 (severe >30). Despite continuous positive airway pressure therapy, he was evaluation by endocrinology for persistent symptoms. Hypogonadism and adrenal insufficiency was diagnosed, hydrocortisone and testosterone patches started, and a magnetic resonance imaging (MRI) brain ordered to rule out pituitary pathology. Psychiatric evaluation was indicated in 2011 for depression and anxiety; mirtazapine and seroquel were started. Furthermore, a neurology consult was done for the development of unexplained tremors. Overall, the patient's opioid regimen was steadily increased from 50 MME/day to 195 MME/day over 25 years.
Upon presentation, he was tremulous, plethoric, and breathing rapidly. The pain was achy, worse with activity, and improved with rest and lying down. On exam, tenderness to palpation and hyperalgesia was generalized and not limited to the low back. Musculoskeletal provocative tests: straight leg raise, FABER, and facet loading were negative. Current medications included escitalopram, gabapentin, baclofen, alendronate, hydrocortisone, testosterone, mirtazapine, montelukast, albuterol, tamsulosin, and zolpidem. Imaging demonstrated intact surgical hardware without evidence of complications. We concluded that his primary pain generator was post-laminectomy syndrome complicated by opioid tolerance and opioid-induced hyperalgesia. We recommended an opioid taper by 10–15% every other week in conjunction with a multimodal treatment plan. We prescribed naloxone per CDC guidelines and oral clonidine for potential withdrawal symptoms. Gradually, we weaned from 195 to 75 MME/day over 3 months while assessing for positive and negative changes in his pain and ability to perform his daily activities. By the time he was weaned to 75 MME/day, we found no worsening of pain or deterioration of functionality as described by the patient.
Our case uniquely highlights many potential adverse sequelae of chronic opioid therapy. Associated with long-term use of opioids, our patient developed well-known adverse effects of opioids such as constipation, hypogonadism, and opioid-induced hyperalgesia (OIH) and other side effects of chronic opioid use such as GERD, adrenal insufficiency, osteoporosis worsening sleep apnea, and urinary stasis complicated by nephrolithiasis necessitating surgical intervention. Multiple interdisciplinary consultants, including cardiology, endocrinology, gastroenterology, psychiatry, neurology, sleep medicine, and urology were involved in his care. The concurrent use of several pharmacological agents complicated his clinical presentation. This clinical course entailed a large social and financial health care burden directly resulting from relying solely on long-term opioid prescriptions for pain control without adequate management of side effects and risks.
OIH is a paradoxical response whereby a patient receiving opioids for the pain management may become more sensitive to certain painful stimuli [ 6]. Its incidence has been reported as high as 27% [ 7]. OIH can often be challenging to differentiate from withdrawal or tolerance. The pain from OIH differs from tolerance in that it does not improve when higher doses of opioids are administered, as noted in our case. Treatment strategies include gradually weaning opioids to lower doses or completely eliminating opioids while establishing a therapeutic relationship with the patient and safely and effectively caring for pain [ 6]. Frequent office visits and treatment strategies that utilize multimodal non-opioid adjuvant medications are also integral. Interventional pain procedures and behavior therapies can further assist with a successful wean from their opioids.
Opioid-induced activation of enteric neurons in the GI tract decreases forward motility, which may lead to abnormalities throughout the digestive system as seen with GERD, gastroparesis, and severe constipation in our patient. Opioids decrease esophageal peristalsis and sphincter activity which can contribute to worsening of GERD. Other causes of reflux to be considered include NSAID use, smoking, pregnancy, obesity, and dietary choices. An appropriate bowel regimen should always be considered when utilizing opioid therapy.
Opioids are known to cause central sleep apnea, which may worsen existing sleep-disordered breathing from obstructive sleep apnea, abnormal breathing patterns, and hypoxemia. One recent literature review reported the prevalence as high as 42% to 85% [ 8]. A dose dependent association between opioids and the degree of severity of sleep-disordered breathing has been noted [ 8]. Although it is difficult to ascertain if our patient’s opioid use directly contributed to his OSA, sleep-disordered breathing should be considered when initiating or maintaining opioid prescriptions. Naloxone prescribing and extensive education regarding its use may be considered as a risk mitigation strategy for patients with concurrent sleep apnea and opioid medication use. The CDC recommends naloxone for high-risk opioid patients, including those with a history of overdose or substance use disorder, high daily doses (>50 MME/day), or concurrent benzodiazepine prescription [5].
Both endogenous and exogenous opioids can modulate gonadal function primarily by acting on opioid receptors in the hypothalamus [ 5, 9]. Opioids decrease release or disrupt the normal pulsatility of gonadotropin releasing hormone secretion, resulting in a reduction of the release of luteinizing hormone and follicle stimulating hormone from the pituitary gland, and of testosterone or estradiol from the gonads [ 10]. The reported prevalence of opioid-induced hypogonadism ranges from 21% to 86% [ 11]. This condition remains under-reported and undertreated. Hypogonadism can lead to erectile dysfunction, impotence, a loss of muscle mass in men, and irregular periods or amenorrhea in women. Symptoms can also include flushing, sweating, decreased libido, infertility, osteopenia, osteoporosis, and depression [ 8].
In summary, as for many pain therapies there is a lack of evidence to support the use of long-term opioid treatment for chronic pain and evidence that risk management and multi-modal treatment can improve outcomes. If using opioids we recommend vigilance for adverse sequelae and consideration of personalized multimodal treatment to help reduce dose escalation and to wean from high doses.
Question 1: A 35-year-old female presented with amenorrhea, which started after a second childbirth a year ago. Medical history is remarkable for 5 years of chronic back pain managed with hydrocodone—acetaminophen 10/325 mg orally three times a day. Due to worsening pain during her pregnancy, she was transitioned to oxycodone 20 mg three times a day on which she has remained since. What is the likely diagnosis?
Correct answer: Opioid-induced hypogonadism. While not widely recognized, the prevalence ranges from 19% to 86% in both males and females [ 3]. Opioids bind to opioid receptors in the hypothalamus to disrupt or reduce the normal amount of gonadotropin releasing hormone released, thus altering the levels of luteinizing hormone and follicle stimulating hormone. The levels of testosterone and estradiol from the gonads is also affected. Some reports suggest opioids increase the levels of prolactin thereby reducing the amount of testosterone secreted. Chronic opioid usage can therefore manifest as amenorrhea and decreased sexual drive.
Obesity, low body mass index, excessive exercise, and use of contraceptives are all potential risk factors for amenorrhea. While this patient’s main complaint is amenorrhea, the question stem does not suggest any of these risk factors in her medical history and presentation. Elevated use of opioids is the only usual aspect of her history. Fibroids or uterine scarring could be other differentials if her pregnancies were complicated.
Question 2: A 60-year-old male presents with low back pain s/p five back surgeries over the last 10 years. Medications include oxycodone-acetaminophen 10-325 mg every 4 hours and MS Contin 60 mg every 8 hours for many years. Pain score 8/10 despite gradual escalations in opioid regimen. His primary care physician feels a pain specialist would better manage his regimen. Physical exam demonstrates diffuse hyperalgesia over the lumbar spine, upper back, shoulders, arms, and legs. Diagnosis?
Correct answer: Opioid-induced hyperalgesia. A paradoxical response to opioid exposure, which presents as a state of nociceptive sensitization. The patient manifests signs and symptoms of increased sensitivity due to a lowered pain threshold.
Malingering: Behavior with the intentional production of false or exaggerated symptoms with secondary gains such as avoidance of work, obtaining drugs, or evading criminal prosecution.
Physical dependence: A physiologic condition when a sudden decrease in opioid use triggers a withdrawal state.
Addiction: A condition influenced by psychological, social, and environmental factors where the patient may exhibit drug-seeking behaviors, compulsive behaviors, and repeated use of the medication despite harmful consequences.