Opioid Analgesics

Article Author:
Brandon Cohen
Article Editor:
Charles Preuss
Updated:
12/11/2019 11:25:19 PM
PubMed Link:
Opioid Analgesics

Indications

Opioid analgesia is indicated for the management of pain in patients where an opioid analgesic is appropriate. What, exactly, the term appropriate constitutes has been a recently contentious issue. Center for Disease Control and Prevention's 2016 guidelines for prescribing opioids for chronic pain state that "clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate." In the same guidelines, the CDC defines the indication of opioid use for acute pain, stating that "when opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed."[1][2][3][4][2]

Mechanism of Action

Opioids act both presynaptically and postsynaptically to produce an analgesic effect. Presynaptically, opioids block calcium channels on nociceptive afferent nerves to inhibit release of neurotransmitters such as substance P and glutamate which contribute to nociception. Postsynaptically, opioids open potassium channels which hyperpolarize cell membranes, increasing the required action potential to generate nociceptive transmission. The mu, kappa and delta opioid receptors mediate analgesia spinally and supraspinally.[5]

Also, some opioid agents can affect serotonin kinetics in the presence of other serotonergic agents. The proposed mechanism for this is through either weak serotonin reuptake inhibition and increased the release of intrasynaptic serotonin through inhibition of gamma-aminobutyric acidergic presynaptic inhibitory neuron on serotonin neurons. These opioids include tramadol, oxycodone, fentanyl, methadone, dextromethorphan, meperidine, codeine, and buprenorphine. These opioids have the potential to cause serotonin syndrome and should be used cautiously with other agents with serotonergic activity.

Opioids such as methadone also have activity at the N-methyl-D-aspartate (NMDA) receptor. Methadone binds to the NMDA receptor and antagonizes the effect of glutamate, which is theorized to explain why methadone has efficacy in the treatment of neuropathic pain above other opioids.[6]

Administration

Opioid analgesics can be administered through a variety of drug dosage forms. Most opioids are available in oral formulations, including both immediate release or extended-release tablets. Buprenorphine is also commonly used in sublingual films in medications such as Suboxone, a medication commonly used for mitigation of symptoms related to opioid withdrawal in addicts attempting to detoxify. Codeine is also commonly given in oral suspensions such as in codeine cough syrup with or without antihistamines such as promethazine. Intravenous formulations of opioids such as morphine, hydromorphone, and fentanyl very frequently are used for pain control or sedation in an inpatient setting. Fentanyl also exists formulated for transdermal patches for extended absorption. Rectal formulations of morphine and hydromorphone are also commonly given to patients who cannot tolerate medications by mouth. Methadone is also commonly given orally, subcutaneously, or intramuscularly if there is a concern for patient noncompliance and the possibility of illicit sale or distribution of controlled substances. Morphine can also commonly given epidurally for the management of acute pain, and intrathecally in the form of implantable spinal pumps for management of chronic pain and palliative care.

Adverse Effects

Because of the distribution of opioid receptors both within and outside the nervous system, opioid analgesics produce a broad spectrum of adverse effects including dysphoria, euphoria, sedation, respiratory depression, constipation, suppression of endocrine systems, cardiovascular disorders (e.g., bradycardia), convulsion, nausea, vomiting, pruritus, and miosis. In addition to these, long-term use of opioid analgesia can produce tolerance and in some cases opioid-induced hyperalgesia and/or allodynia.[7]

Also as mentioned above, opioids with serotonergic activity such as tramadol, oxycodone, fentanyl, methadone, dextromethorphan, meperidine, codeine, and buprenorphine have the potential to cause serotonin syndrome when used with other agents with serotonergic activity.[8] Therefore, coadministration with other serotonergic active medications should be done cautiously or avoided entirely.

Contraindications

Some relative contraindications to opioid analgesics include increased the risk of prescription abuse. Several risk factors have been identified.

These include:

  • Family or personal history of substance abuse
  • Young age
  • History of legal problems
  • Frequent contact with high-risk individuals or environments
  • History of previous problems with employers, family, and friends
  • History of risk-taking and thrill-seeking behavior
  • Smoking cigarettes and regularly using other substances that lead to dependence
  • History of major depression or anxiety
  • Multiple psychosocial stressors
  • History of childhood abuse
  • Previous drug and/or alcohol rehabilitation.

Also, other opioid-specific toxicities exist which may preclude their use in certain populations. For example, as mentioned above, opioids with serotonergic activity have the potential to lower seizure threshold, and should, therefore, be used cautiously or avoided entirely in patients with a history of seizure disorder in order to avoid causing or worsening seizures. Opioids such as methadone which have the potential to prolong QTc interval should be used cautiously or avoided entirely in patients with Long QT syndrome.

Monitoring

The degree of monitoring for patients prescribed opioid analgesics is highly provider-dependent. All providers should see patients for routine follow-up visits that include a history and physical exam to monitor for adverse effects listed previously. Many providers employ a wide variety of other tactics to monitor for signs of abuse including assessment surveys, state prescription drug monitoring programs, frequent visits with urine toxicology screens, use of adherence check-lists, motivational counseling, and pill counts.[9]

Toxicity

Opioids can cause fatal overdose through respiratory depression, especially when combined with other sedatives such as alcohol and benzodiazepines. Patients with altered mental status, depressed respiration, and constricted pupils should be suspected of suffering from an acute opioid-related overdose which can be fatal if untreated.[10] Overdose can be reversed by agents such as naloxone which can be given intravenously, intramuscularly, or intranasally. Naloxone is a centrally-acting pure opioid antagonist with a high affinity which quickly counteracts opioid action. Naloxone can be given in small repeated doses and titrated to desirable response. Naloxone is active for 30 to 60 minutes before being deactivated by the liver, which means naloxone may have to be repeatedly given for overdose of long-acting opioid analgesic dosage forms.

Other opioid-specific toxicities which are worth mentioning also exist. For example, methadone carries a risk of QTc prolongation and in some cases Torsades de Pointes. Also, opioids that have a serotonergic action, for example, tramadol, can cause seizures and serotonin syndrome.

Enhancing Healthcare Team Outcomes

The healthcare team, e.g., physicians, nurses, pharmacists, etc. needs to work together in order to accurately address pain control in their patients.  The healthcare team should schedule their patients for routine follow-up visits that include a history and physical exam to monitor for adverse drug effects and drug abuse. Monitoring for signs of drug abuse is a very important responsibility for the healthcare team because of the epidemic rates of drug abuse world-wide, e.g., USA which lead to death because of respiratory depression. Methods for monitoring drug abuse as well as drug diversion include the following examples: assessment surveys, state prescription drug monitoring programs, urine  screening, adherence check-lists, motivational counseling, and dosage form, e.g., tablet counting.


References

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[7] Crockett SD,Greer KB,Heidelbaugh JJ,Falck-Ytter Y,Hanson BJ,Sultan S, American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019 Jan;     [PubMed PMID: 30340754]
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[9] Dowell D,Haegerich TM,Chou R, CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. JAMA. 2016 Apr 19;     [PubMed PMID: 26977696]
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