Treatment of Pain

The oral route for opioids may be used for treatment of acute pain if the patient is able to tolerate oral drugs.

The oral or transdermal route is preferred for long-term use; both are effective and provide stable blood levels. Modified-release oral and transdermal forms allow less frequent dosing, which is particularly important for providing overnight relief.

Transmucosal (sublingual)

The IV route provides the most rapid onset and thus the easiest titration, but duration of analgesia is short. Large, rapid fluctuations in blood levels (bolus effect) can lead to toxicity at peak levels early in the dosing interval or later to breakthrough pain at trough levels. Continuous IV infusion, sometimes with patient-controlled supplemental doses, eliminates this effect but requires an expensive pump; this approach is used most often for postoperative pain.

The IM route provides analgesia longer than IV but is painful, and absorption can be erratic; it is not recommended except when a single dosage is anticipated and a patient does not have IV access.

Intraspinal

Long-term continuous subcutaneous infusion can be used, particularly for cancer pain.

Initial dose in an opioid-naive patient is usually the lowest available starting dosage of the immediate-release formulation, and it is increased incrementally by the smallest amount practical until analgesia is satisfactory or adverse effects limit treatment. Long-acting opioids should not be used as first-line treatment in opioid-naive patients and should not be prescribed for intermittent use.

Older patients are more sensitive to opioids and are predisposed to adverse effects; opioid-naive older patients typically require lower doses than younger patients. Neonates, especially when premature, are also sensitive to opioids because they lack adequate metabolic pathways to eliminate them.

Sedation and respiratory rate are monitored when opioids are given parenterally to relatively opioid-naive patients. Opioid therapy, particularly for opioid-naive patients, should start with a short-acting drug because many longer-acting opioids are given at higher doses and their adverse effects (including serious ones such as respiratory depression) last longer.

For moderate, transient pain, an opioid may be given as needed. For severe or ongoing pain, doses should be given regularly, without waiting for severe pain to recur; supplemental doses are given as needed when treating cancer pain. The doses for patients with chronic noncancer pain are typically decided case by case.

Patients with dementia cannot use patient-controlled analgesia, nor can young children; however, adolescents often can.

Treatment of chronic pain with opioids should be done only when other options have been tried and are not effective. During long-term treatment, the effective opioid dose can remain constant for prolonged periods. Some patients need intermittent dose escalation, typically in the setting of physical changes that suggest an increase in the pain (eg, progressive neoplasm). In such cases, fear of tolerance should not inhibit appropriate early, aggressive use of an opioid.

methadone should be started at a low dose, use should be closely monitored, and dose should be increased slowly (≤ once a week), especially in an unmonitored outpatient setting. Because methadone can prolong the cardiac QT interval, the QTc interval should be assessed by ECG before methadone initiation and before and after any significant change in methadone dosing. Methadone should be used with extreme caution, if at all, in patients taking other drugs that may affect the QT interval.

If a previously adequate dose becomes inadequate, that dose must usually be increased to control pain.

In opioid-naive patients, common adverse effects at the start of therapy include

• Sedation and mental clouding

• Nausea and vomiting

• Constipation

• Itching

• Respiratory depression

• Myoclonus

In older patients, opioids tend to have more adverse effects (commonly, constipation and sedation or mental clouding). Falls are a particular risk in older patients. Opioids may cause urinary retention in men with benign prostatic hyperplasia.

Opioids should be used cautiously in patients with certain disorders:

• Hepatic disorders because drug metabolism is delayed, particularly with modified-release preparations

• COPD because respiratory depression is a risk

• Untreated obstructive sleep apnea because respiratory depression is a risk

• Some neurologic disorders, such as dementia and encephalopathy, because delirium is a risk

• Severe renal insufficiency

Sedation is common. Patients should not drive and should take precautions to prevent falls and other accidents for a period of time after initiation of opioids and after an increase in dose until they can judge the drug's effect on their ability to do these types of activities. Patients and family members should be instructed to contact one of their practitioners if patients experience excessive or persistent sedation. If sedation impairs quality of life, certain stimulant drugs may be given intermittently (eg, before a family gathering or other event that requires alertness) or, to some patients, regularly. Drugs that can be effective are

Most patients who overdose or have respiratory depression are misusing the drug (not taking it as prescribed) or taking high doses (> 100 OMME). However, most opioid overdoses are unintentional, and respiratory depression can occur when the opioid dose is low (< 20 OMME).

Risk of overdose or respiratory depression is higher when patients

• Have comorbidities that affect hepatic or renal metabolism

Risk factors for respiratory depression also include

• History of stroke, renal disease, heart failure, or chronic pulmonary disease

• Untreated or undertreated obstructive sleep apnea or chronic obstructive pulmonary disease (COPD)

• Substance use disorder

• Psychiatric disorders

• Concurrent use of some common psychoactive drugs

Modifiable risk factors for overdose or respiratory depression should be managed; strategies include

• Treating sleep apnea

• Advising patients not to drink alcohol when they take the opioid

• Not prescribing benzodiazepines with opioids when possible

• Not prescribing long-acting opioids when possible

• Assessing the risk of overdose or serious opioid-induced respiratory depression using the Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD)

Nausea can be treated with one of the following:

Itching

Constipation is common among patients who take opioids for more than a few days. Preventive treatment should be considered for all patients when opioids are started, especially for predisposed patients (eg, older patients, immobile patients). Dietary fiber and fluids should be increased (but are rarely sufficient alone), and initially, a stimulant laxative2). Effective drugs include

Although tolerance to opioid-induced sedation, mental clouding, and nausea usually develops within days, tolerance to opioid-induced constipation and urinary retention usually occurs much more slowly. Any adverse effect may be persistent in some patients; constipation is particularly likely to persist.

For urinary retention

Neuroendocrine effects, typically reversible hypogonadism, are possible. Symptoms may include fatigue, loss of libido, infertility due to low levels of sex hormones, and, in women, amenorrhea. Low levels of androgens also lead to osteoporosis. Patients taking long-term opioid therapy require intermittent bone density testing.

(See also Centers for Disease Control and Prevention: 2019 Annual surveillance report of drug-related risks and outcomes—United States. Surveillance special report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.)

Opioids are the leading cause of accidental death and fatal drug overdose in the US. Risk of fatal drug overdose increases significantly when opioid analgesics are used with benzodiazepines. Also, rates of misuse, diversion, and abuse (aberrant drug-taking behaviors) are increasing.

Opioid misuse may be intentional or unintentional. It includes any use that contradicts medical advice or deviates from what is prescribed.

Diversion involves selling or giving a prescribed drug to others.

Abuse refers to recreational or nontherapeutic use (eg, euphoria, other psychotropic effects).

Up to one third of patients taking long-term opioids for chronic pain may misuse prescribed opioids (not use them as directed) or may abuse them.

Addiction, typically marked by impaired control and craving, refers to compulsive use despite harm and negative consequences. Some definitions of addiction include tolerance (an increasingly higher dose is required to maintain the same level of analgesia and efficacy over time) and withdrawal (discontinuation of the drug or a significant decrease in the dose causing withdrawal symptoms). However, both of these characteristics are expected physiologic effects of opioid therapy and therefore not useful in defining opioid addiction.

Opioid use disorder is preferred over the term addiction. Opioid use disorder is defined as compulsive, long-term self-administration of opioids for nontherapeutic purposes, causing significant impairment or distress. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides specific criteria for diagnosing this disorder. Opioid use disorder is diagnosed if the pattern of use causes clinically significant impairment or distress and if ≥ 2 of the following are observed over a 12-month period:

• Taking opioids in larger amounts or for a longer time than intended

• Persistently desiring or unsuccessfully attempting to decrease or control opioid use

• Spending a great deal of time trying to obtain or use the opioid or recover from its effects

• Craving or having a strong desire or urge to use opioids

• Using opioids repeatedly resulting in failing to meet obligations at work, home, or school

• Continuing to use opioids despite having persistent or recurrent social or interpersonal problems caused or exacerbated by opioid use

• Giving up or reducing important social, work, or recreational activities because of opioids

• Continuing to use opioids in physically hazardous situations

• Continuing to use opioids despite having a persistent or recurrent physical or psychologic disorder caused or worsened by opioids

• Having tolerance to opioids

• Having opioid withdrawal symptoms

Tolerance and withdrawal (secondary to the development of physical dependence) are expected in patients who take opioids under appropriate medical supervision Thus, these findings in a patient being medically managed with opioid therapy do not count as part of the criteria of opioid use disorder.

Risk of opioid use disorder depends on frequency of use and dose (3):

• 0.004%: No regular opioid use

• 0.7%: Use of low-dose opioids (< 36 mg/day OMME)

• 6.1%: Use of high-dose opioids (> 120 mg/day OMME)

• 2 to 15%: In other studies (not stratified by dose)

When considering prescribing opioid therapy, particularly long-term therapy, clinicians should evaluate patients for risk factors for abuse and diversion and counsel them against intentional and inadvertent misuse. Before opioid therapy is started, clinicians should obtain informed consent and assess the patient's risk of developing opioid use disorder.

Risk factors for developing opioid use disorder include

• Patient history of alcohol or drug abuse

• Family history of alcohol or drug abuse

• Major psychiatric disorder (current or past)

• Use of psychoactive drugs

• Younger age (< 45)

Screening tools can help identify patients at higher risk of opioid use disorder; the opioid risk tool (ORT) may be the best. However, no risk assessment tool is sufficient to determine whether treating a patient with opioids is safe or has a low risk. Therefore, all patients being treated with opioids should be monitored closely during treatment to make sure opioid therapy is used safely.

Routine monitoring should include periodic unannounced urine drug screens to check for the presence of the prescribed drug and absence of illicit drugs.

Unannounced screens are more likely to identify aberrant use or misuse but are more challenging to incorporate into a clinic's workflow. Current recommendations are to do urine drug screens as follows:

• At initial prescription

• At least annually

• More frequently if risk is high or concerns develop

The patient's history of controlled substance use should be reviewed using information from state prescription drug monitoring programs (PDMPs). Current recommendations include routine screening using the PDMP as follows:

• When opioids are initially prescribed

• When each refill is prescribed or at least every 3 months

Routine PDMP inquiries help clinicians make sure a single prescribing physician and pharmacy are used.

Even when risk factors for developing an opioid use disorder are present, treatment may still be appropriate; however, clinicians should use more stringent measures to prevent abuse and addiction (4). Measures include

• Prescription of only small amounts (requiring frequent visits for refills)

• Urine drug screening to monitor treatment adherence (ie, to confirm that patients are taking the drugs and not diverting them)

• No refills for “lost” prescriptions

• Use of tamper-resistant opioid formulations that have been developed to deter abuse by chewing or by crushing and injecting oral preparations

Clinicians may need to refer problematic patients to a pain specialist or a substance use specialist experienced in pain management.

When the opioid is first prescribed, clinicians should provide relevant information to patients. Clinicians also ask patients to sign a contract that specifies the measures that will be taken to ensure safe use of ongoing prescribing and use and the consequences of a history or an evaluation (eg, urine drug screening, prescription drug monitoring) that suggests aberrant use, misuse, abuse, or diversion (ie, opioid tapering). Clinicians should go over the contract with patients to make sure they understand what is required. Signing and thus agreeing to the contract is required before patients can take opioids. Patients should also be told that nonopioid pain management strategies will be continued and that they may be referred to a substance use specialist.

To avoid misuse of their drug by others, patients should keep opioids in a safe place and dispose of any unused drugs by returning them to the pharmacy.

All patients should be counseled regarding the risks of combining opioids with alcohol and anxiolytics and self-adjustment of dosing.

Opioid antagonists are opioid-like substances that bind to opioid receptors but produce little or no agonist activity. They are used mainly to reverse symptoms of opioid overdose, particularly respiratory depression.

acts in < 1 minute when given IV and slightly less rapidly when given IM. It can also be given sublingually or endotracheally. Duration of action is about 60 to 120 minutes. However, opioid-induced respiratory depression usually lasts longer than the duration of antagonism; thus, .

The dose for acute opioid overdosage is 0.4 mg IV every 2 to 3 minutes as needed (titrated to adequate respirations, not alertness). If repeated doses are necessary, the dose can be increased (to a maximum of 2 mg IV per dose). If there is no response after 10 mg has been given, the diagnosis of opioid toxicity should be reconsidered.

, an orally bioavailable opioid antagonist, is given as adjunctive therapy in opioid and alcohol addiction. It is long-acting and generally well-tolerated.

1. 1. Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain—United Stat 2016. JAMA 315 (15):1624–1645, 2016. doi: 10.1001/jama.2016.1464

2. 2. Argoff CE, Brennan MJ, Camilleri M, et al: Consensus recommendations on initiating prescription therapies for opioid-induced constipation. Pain Med 16 (12):2324-2337, 2015. doi: 10.1111/pme.12937

3. 3. Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain--United States, 2016. JAMA 315 (15):1624–1645, 2016. doi: 10.1001/jama.2016.1464

4. 4. Babu KM, Brent J, Juurlink DN: Prevention of opioid overdose. N Eng J Med 380:2246–2255, 2019. doi: 10.1056/NEJMra1807054