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 will outweigh risks to the patient. When using opioids, it should be in combination 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]

Opioids act both presynaptically and postsynaptically to produce an analgesic effect. Presynaptically, opioids block calcium channels on nociceptive afferent nerves to inhibit the 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 theoretically explains why methadone has efficacy in the treatment of neuropathic pain above other opioids.[6]

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 the mitigation of symptoms related to opioid withdrawal in addicts attempting to detoxify. Codeine is also widely 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 non-compliance and the possibility of illicit sale or distribution of controlled substances. Morphine can also be given epidurally for the management of acute pain, and intrathecally in the form of implantable spinal pumps for the management of chronic pain and palliative care.

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]

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.

Some relative contraindications to opioid analgesics include increased risk of prescription misuse. Several risk factors exist. 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 specific populations. For example, as mentioned above, opioids with serotonergic activity have the potential to lower the seizure threshold, and should, therefore, be used cautiously or avoided entirely in patients with a history of seizure disorder 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.