Opioid-Related Side Effects

Introduction

• Opioid medications are potent analgesics used for acute and chronic pain management.^1-4
• Although they are effective analgesics, opioids are also associated with a variety of side effects, which can range from mild to life-threatening, and often limit dosing or lead to early discontinuation.^1,2
• Potential side effects include sedation, cognitive impairment, ventilatory impairment, nausea, constipation, hypogonadism, tolerance, dependence, and opioid use disorder (OUD).^1-9
• Given the potential risks, careful prescribing, close monitoring, and thorough patient education are essential.

Mechanism

• Opioids exert their effects by binding to receptors in the central and peripheral nervous system.^1,2
• Please see the OA summary on Opioids: Basics for more details. Link
• Opioids exert their analgesic effects primarily through interaction with opioid receptors (mu, delta, and kappa receptors) in the central nervous system (CNS).^1,4
• Activation of opioid receptors modulates pain perception but also triggers various physiological responses, leading to a multitude of side effects.
• The manifestation of side effects and people’s sensitivity to them is related to comorbidities, genetics, age, and medications co-prescribed.⁹

Side Effects

CNS Side Effects

• CNS side effects include sedation, decreased level of consciousness, dizziness, and cognitive impairment.^5,6
• Sedation occurs via direct action in the CNS and the hypercarbia resulting from opioid-induced ventilatory impairment.^5,6
• Sedation is most concerning when initiating opioid therapy or escalating doses.⁵
• Cognitive impairment is a continuum that can vary from inattention to extreme confusion and delirium.
• Concomitant use of opioids and centrally acting medications such as benzodiazepines can exacerbate the risk of CNS side effects.^5,6
• These side effects can interfere with daily functioning, leading to falls and accidents, especially in frail populations.
• Treatment options include observation, reducing the dose of opioids, switching to a different opioid, or using alternative analgesics.
• Should all potential confounders be controlled and opioid therapy continuation needed, the use of psychostimulants such as methylphenidate or modafinil can be considered.⁹

Cardiopulmonary Side Effects

Ventilatory Impairment

• Ventilatory impairment occurs less frequently than other side effects (such as gastrointestinal (GI) side effects) but has more fatal consequences.²
• It is mediated mostly by mu receptors in the pre-Botzinger complex.²
• Mu receptor activation at these sites leads to changes in respiratory rhythm and hypercapnic ventilatory response.⁶
• Please see the OA summary on Opioid-induced Ventilatory Impairment for more details. Link

GI Side Effects

Nausea/Vomiting

• Activation of opioid receptors in the chemoreceptor trigger zone, vestibular apparatus, and GI tract can lead to nausea and vomiting.^1,2
• If nausea develops during initiation of opioid therapy, tolerance usually builds quickly, and persistent nausea is rare.⁹
• If nausea persists, opioid rotation and changing the route of administration seem to reduce nausea and vomiting.²
• Chronic nausea can be treated with first-line agents such as dopamine antagonists (example metoclopramide, prochlorperazine) or serotonin receptor antagonists (example ondansetron). If symptoms persist, atypical antipsychotics such as risperidone or olanzapine may be considered.⁹

Constipation

• Constipation is one of the most common side effects related to opioid use that is mediated by activation of the mu-opioid receptor in the enteric nervous system.^1,2
• Opioid-induced constipation (OIC) is a clinical diagnosis and there are diagnostic criteria such as the ROME-IV criteria.⁹
• Constipation occurs as there is reduced motility (due to decreased peristalsis) and changes in intestinal fluid absorption and electrolyte secretion (longer transit time leads to excess water and electrolyte resorption).^1,2,9
• Different opioid formulations cause constipation to various degrees. It is thought that transdermal opioids have fewer constipating effects in comparison to oral formulations.⁹
• Unfortunately, there is no tolerance or ceiling effect to constipation.^1,2,7
• Treatment centers around prevention via the use of laxatives and nonmedication changes, such as increased fiber, movement, and hydration.^2,9
• OIC that is refractory to traditional laxatives should be treated with opioid receptor antagonists such as methylnaltrexone, naloxegol, naldemedine, and alvimopan.⁹

Endocrine Side Effects

• Opioids affect the function of the hypothalamic pituitary adrenal axis.⁹
• Side effects include hypogonadism and adrenal insufficiency.^1,9
• Chronic opioid use is associated with a decrease in testosterone, estrogen, cortisol, luteinizing hormone, and gonadotropin-releasing hormone.¹
• Hypogonadism leads to sexual dysfunction, poor sleep, fatigue, depression, osteoporosis, and infertility.⁹
• Hormone replacement has not been established as a gold standard treatment.

Immune Side Effects

• Chronic opioid use can modulate the immune system, increase infection susceptibility, and impair wound healing.¹
• Opioid-related immunosuppression impairs neutrophil chemotaxis and reduces natural killer cell cytotoxicity.⁹

Pruritus-Related Side Effects

• Opioid-induced pruritus is a phenomenon where patients experience itching postopioid administration, which can vary from mild to severe.
• Pruritus is more common with neuraxial opioid administration compared to parenteral or oral administration.
• It has both central and peripheral mechanisms of origin.^1,9
  • Centrally, opioids activate receptors in the CNS to promote itching that is not histamine-mediated.^1,2
  • Peripherally, opioids can lead to mast cell degranulation of histamine.^1,2
• Some opioids, such as morphine, have a higher propensity for causing pruritus.
• Treatment can include opioid rotation, nalbuphine, or low-dose naloxone.^2,9

OIH

• OIH is a condition in which prolonged opioid use leads to increased pain sensitivity instead of the intended pain relief.³
• It is a well-established phenomenon in a laboratory setting, but its clinical relevance is still highly debated.⁹
• OIH occurs secondary to central sensitization, which is mediated by the release of proinflammatory cytokines, glial cell activation, increased N-methyl-D-aspartate (NMDA) receptor activity, upregulation of nociceptive pathways, and disruption of the endogenous pain modulation systems.³
• OIH typically manifests as disproportionate and widespread pain that is not clearly related to the original mechanism of injury.³
• To diagnose OIH, it is essential to rule out clinically worsening pain and tolerance.³
• For opioid tolerance, increased opioid doses are needed to achieve the pain relief, yet in OIH, an increase in opioid dose will worsen pain.³
• Treatment for OIH entails opioid tapering, use of NMDA antagonists (ketamine and methadone), and maximization of nonopioid adjuvant medications (anticonvulsants, antidepressants, and non-steroidal anti-inflammatory drugs).³

Tolerance, Dependence, and Addiction

Tolerance

• Tolerance is a phenomenon that occurs with prolonged use of opioids.⁷
• Tolerance occurs when there is a decreased analgesic response to the current opioid dose, requiring escalating opioid doses.^1,3
• On a cellular level, there is an increase in inactive receptors on the membrane (due to internalization and desensitization) with prolonged opioid use.^2,8
• Management of tolerance entails opioid rotation and the addition of adjuvant medications to the pain regimen.²
• Please see the OA summary on Opioid Rotation and Equianalgesic Dosing for more details. Link

Dependence

• Dependence is a phenomenon where patients develop withdrawal symptoms with the abrupt discontinuation of opioids.¹
• Withdrawal symptoms include abdominal cramps, diarrhea, runny nose, tearing, yawning, sweating, agitation, and muscle aches.^4,8

Addiction and OUD

• OUD is defined by the continued use of opioids despite harmful consequences.⁸
• The symptoms of opioid tolerance and withdrawal, with uncontrolled intake and cravings are the core symptoms of OUD.
• Risk factors for addiction include:
  • access to opioids and other controlled substances;
  • easy diversion of these drugs;
  • curiosity about patients’ experiences with these drugs;
  • detail-oriented personality type;
  • high levels of stress;
  • younger than 35 years of age;
  • alcohol and tobacco abuse; and
  • history of mental illness.
• OUD is a type of substance use disorder (SUD) characterized by addiction to opioids, which can occur secondary to opioid tolerance, need to combat opioid withdrawal, desire to experience euphoria, and uncontrolled cravings.⁸
• One way opioids lead to cravings is due to their effect in the brain’s reward system by increasing the release of dopamine in the mesolimbic system.^4,8
• OUD is a costly and deadly disease that was brought to public attention beginning in the late 1990s via the opioid epidemic.^4,8
• Please see the OA summary on Substance Use Disorder Among Anesthesia Providers for more details. Link
• Both classic and molecular genetic research have provided evidence that opioid addiction is not only environmental but also at least partly heritable.⁸
• Treatment of OUD involves pharmacologic and behavioral medicine modalities.^4,8
• Medications used to treat OUD fall into three categories:^4,8
  • Full opioid agonists (example: methadone)
• They work on mu receptors to decrease withdrawal and cravings.⁴
• Their half-life ranges from 15 to 22 hours.⁴
• There is risk of respiratory depression.⁴
  • Partial opioid agonists (example: buprenorphine)
    • They work on mu receptors to decrease withdrawal and cravings.⁴
    • Their half-life ranges from 20 to 70 hours.⁴
    • Since these are partial agonists, respiratory depression is uncommon.⁴
    • They can be combined with antagonists to treat chronic abuse. When crushed and injected, they will precipitate withdrawals.⁴
  • Opioid antagonists (example: naloxone)
    • They work on mu, kappa, and delta receptors to treat opioid overdose.⁴
• Unfortunately, as with every SUD, relapses do occur despite treatment.