**7. Risk of opioids**

After the addition of nonopioids and possible adjuvants, the WHO's analgesic ladder calls for low to strong opioids. However, if a patient is in severe acute pain, it is reasonable to start therapy with all three types of analgesics and then rapidly de‐escalate to a lower step on the analgesic ladder [9]. When treating chronic pain, opioids should never be utilized as first‐line agents outside of cancer or palliative care. Opioids have only been shown in the literature to have a short‐term improvement in pain and carry a high risk for serious side effects and possibly even death [6]. Before initiating therapy, clinicians and patients should have a dis‐ cussion regarding expected goals and potential risks. Goals should include how efficacy will be measured for both pain relief and functionality and what measures will indicate contin‐ ued treatment. Patients should also be informed that opioids only show a short‐term benefit in relieving pain and long‐term efficacy is lacking. Expectations should be that opioids will likely never provide complete relief.

The addition of opioids to a chronic pain regimen should be considered carefully. Patients do not need to fail nonopioids or adjuvants prior to initiating opioids, benefits must simply out‐ weigh the risks of starting opioid therapy [1, 8]. Another way to consider this is that opioids should be considered in patients with severe disabling pain that is likely not to be relieved from nonopioids and adjuvants alone. The worst risks are with overdose and potentially fatal respiratory depression. Overdose risk is dose dependent, and clinicians should be care‐ ful when doses are escalated. This is particularly important as there is technically no ceiling dose for opioids. Several other factors increase the risk for opioid‐related overdose including methadone use, co‐prescription with benzodiazepines, history of sleep‐disordered breathing, reduced renal or hepatic function, increased age, pregnancy, history of substance abuse and psychiatric illness. Additionally, the risk of opioid‐related overdose is elevated when starting patients on opioid therapy with long‐acting or extended release formulations. For this reason, these dosage forms should only be utilized in opioid‐tolerant patients. Risk mitigation strate‐ gies such as checking prescription refill history, urine drug screening and use of medications specifically for opioid use disorders (methadone, buprenorphine) increase retention in opioid treatment programs.

Prior to starting opioid therapy, the prescriber must fully understand the concepts of opioid abuse (opioid misuse disorders), tolerance and physical withdrawal [6]. Opioid abuse or opioid misuse disorders are described by patterned misuse of opioids that include unsuccessful attempts to curb use and results in social problems at home, work or school. Tolerance is simply a diminished response to a fixed dose of medication with repeated use. Physical dependence is when a medication causes the body to change in a way that when the medication is removed the body produces withdrawal symptoms. Both physical dependence and tolerance can occur in the absence of opioid abuse. When treating a patient, it is necessary to keep these concepts separate and not to assume that because a patient is requiring higher doses of medication or is experiencing withdrawal symptoms that they are abusing opioids. Only after considering all of these things, a prescriber should initiate opioid therapy.

Opioid medications typically exert their analgesic effects through agonism at μ‐, δ‐ and ĸ‐opi‐ oid receptors [33, 34]. Opioid receptors are g‐coupled protein receptors and are most com‐ monly Gi/Go. Once these g‐coupled protein receptors are activated, they decrease adenylyl cyclase activity, decrease calcium conductance and inhibit excitatory neurotransmission. This slows the transmission of pain that impulses both centrally and peripherally. Opioids activate centrally located receptors that play a key role in descending pain pathways and peripher‐ ally in the spinal cord. This spinal cord transmission regulates the relay of nociceptive pain inputs from the periphery to the brain. While all three opioid receptors mediate analgesia, activation of individual receptors will produce different effects [33]. μ‐opioid receptors lower respiratory depression, sedation, euphoria, nausea, constipation and urinary retention. δ‐opi‐ oid agonists have similar effects to those of μ‐opioid agonists. These effects include respira‐ tory depression, constipation and euphoria. While μ‐ and δ‐opioid agonists have very similar effects, ĸ‐opioid agonists have several unique effects. These agents can cause dysphoric, seda‐ tive, diuretic and sometimes aversive effects. An understanding of what receptor an indi‐ vidual opioid will activate will give the provider information in the common side effects that the medication will exhibit.

When acute or chronic low back pain necessitates the need to escalate to a weak opioid, the practitioner has several options to choose from. Drugs that are considered weak opi‐ oids are codeine, hydrocodone and oxycodone when used in combination with nonopioids (sometimes also tramadol), and all other full agonists (morphine, hydromorphone, oxyco‐ done alone, oxymorphone and fentanyl) are considered moderate of strong opioids [15]. Weak opioids should be initiated with caution if the patient already is taking paracetamol at a fixed interval as it increases the risk of overdose. When starting opioid therapy with the intent to continue its long term, this initial phase should be considered a trial and should only be continued or escalated if pain relief occurs [6]. If a patient fails an initial trial of opioids, other agents should be considered for refractory pain. Once on opioid regimen is started, the practitioner should periodically assess the need to continue opioid therapy. If tolerance occurs or pain relief is reduced, the clinician should weight escalating therapy to a moderate or strong opioid versus the increase in risk. It is reasonable to abandon opioid therapy if, after an escalation in therapy, the patient does not experience an increase in anal‐ gesic effect.
