Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, antiseizure drugs, and other central nervous system (CNS)–active drugs may also be used for chronic or neuropathic pain and are first-line therapy for some conditions. Neuraxial infusion, nerve stimulation, and neural blockade can help selected patients.
Cognitive-behavioral interventions may reduce pain and pain-related disability and help patients cope. These interventions include counseling to refocus a patient's thoughts from the effects and limitations of pain to the development of personal coping strategies and may include counseling to help patients and their family work together to manage pain.
Some integrative (complementary and alternative) medicine techniques (eg, acupuncture, biofeedback, exercise, hypnosis, relaxation techniques) are sometimes used, especially to treat chronic pain.
(See also Overview of Pain.)
Nonopioid Analgesics
Nonopioid Analgesics
Class | Drug | Usual Dosage Range* |
|---|---|---|
Indoles | 50–100 mg, followed by 50 mg every 8 hours 75 mg every 12 hours IV or IM | |
200–400 mg every 6–8 hours | ||
25–50 mg every 6–8 hours | ||
150–200 mg every 12 hours | ||
200–400 mg every 6–8 hours | ||
Naphthylalkanone | 1000–2000 mg every 24 hours | |
Oxicam | 20–40 mg every 24 hours | |
Para-aminophenol derivative | 650–1000 mg every 6–8 hours | |
Propionic acids | 200–600 mg every 6 hours | |
50–200 mg every 12 hours | ||
400 mg every 4 hours to 800 mg every 8 hours (maximum: 3200 mg/day†) | ||
25–50 mg every 6–8 hours | ||
250–500 mg every 12 hours | ||
275–550 mg every 12 hours | ||
600–1200 mg every 24 hours | ||
Salicylates | 650–1000 mg every 4–6 hours | |
Choline magnesium trisalicylate | 870 mg every 12 hours | |
250–500 mg every 8–12 hours | ||
750–2000 mg every 12 hours | ||
Fenamates | Meclofenamate | 50–100 mg every 6–8 hours |
250 mg every 6 hours | ||
Pyrazole | Phenylbutazone | 100 mg every 6–8 hours up to 7 days |
Pyrrolo-pyrrolo derivative | 15–30 mg IV or IM every 6 hours or 20 mg orally, followed by 10 mg orally every 4–6 hours for maximum 5 days (assess creatinine every 4–6 doses, particularly in patients who are older or at risk of renal failure [eg, postoperative patients]) | |
Selective COX-2 inhibitor | 100–200 mg every 12 hours | |
COX = cyclooxygenase. | ||
NSAIDs have analgesic, anti-inflammatory, and antiplatelet effects. They inhibit cyclooxygenase (COX) enzymes and thus decrease production of prostaglandins. There are several classes of NSAIDs, which have different mechanisms and adverse effects:
Both COX inhibitors are effective analgesics. Coxibs have the lowest risk of ulcer formation and GI upset. However, when a coxib is used with low-dose aspirin, it may have no GI benefit over other NSAIDs.
If an NSAID is likely to be used only short term, significant adverse effects are unlikely, regardless of the drug used. Some clinicians use a coxib first whenever therapy is likely to be long term (eg, months) because the risk of GI adverse effects is lower. Others limit coxib use to patients predisposed to GI adverse effects (eg, older patients, patients taking corticosteroids, those with a history of peptic ulcer disease or GI upset with other NSAIDs) and to those who are not doing well with nonselective NSAIDs or who have a history of intolerance to them.
All NSAIDs should be used cautiously in patients with renal insufficiency; coxibs are not renal-sparing.
If initial recommended doses provide inadequate analgesia, a higher dose is given, up to the conventional safe maximum dose. If analgesia remains inadequate, the drug should be stopped. If pain is not severe, another NSAID may be tried because response varies from drug to drug. It is prudent during long-term NSAID therapy to monitor for occult blood in stool and changes in the complete blood count (CBC), electrolytes, and hepatic and renal function.
Topical NSAIDs
Opioid Analgesics
“Opioid” is a generic term for natural or synthetic substances that bind to specific opioid receptors in the central nervous system (CNS), producing an agonist action. Opioids are also called narcotics—a term originally used to refer to any psychoactive substance that induces sleep. Opioids have both analgesic and sleep-inducing effects, but the two effects are distinct from each other.
Opioid Analgesics
Drug | Adult Dose* | Pediatric Dose† | Comments | |||
|---|---|---|---|---|---|---|
Opioid agonists in combination products‡ for moderate pain | ||||||
Oral: 30–60 mg every 4–6 hours as needed | — | |||||
Oral: 5–10 mg every 4–6 hours as needed | — | |||||
Opioid agonists for moderate-to-severe pain | ||||||
Transdermal: 12 or 25 mcg/hour every 3 days Transmucosal: 100–200 mcg every 2–4 hours Intranasal: 100–200 mcg every 2–4 hours Parenteral: 25–100 mcg every 30–60 minutes IV or as patient-controlled analgesia | Parenteral: 1–2 mcg/kg/dose IV; may be repeated in 2–4 hours as needed | May trigger less histamine release and thus may cause less hypotension than other opioids Transdermal: When used in cachectic patients, may result in erratic absorption and blood levels Supplemental analgesia required at first because peak analgesia does not occur until 18–24 hours after application May take many hours for adverse effects to resolve after removing patch Short-acting transmucosal and intranasal forms: Used for breakthrough pain in opioid-tolerant adults and for conscious sedation in children IV form: Sometimes used for procedural sedation | ||||
Oral immediate release: 2–4 mg every 4–6 hours Oral extended-release: 8–32 mg every 24 hours Oral liquid: 2.5–10 mg every 4–6 hours Parenteral: 0.2–1 mg every 4–6 hours or as patient-controlled analgesia Rectal: 3 mg every 6–8 hours | — | Short half-life Rectal form: Used at bedtime | ||||
Oral: 2 mg every 6–8 hours Parenteral: 1–2 mg IM or subcutaneously every 6–8 hours; 1 mg IV every 3–6 hours | — | Long half-life | ||||
Oral: 50–300 mg every 4 hours Parenteral: 50–150 mg IV or IM every 4 hours as needed | — | Not preferred because its active metabolite (normeperidine) causes dysphoria and central nervous system excitation (eg, myoclonus, tremulousness, seizures) and accumulates for days after dosing is begun, particularly in patients with renal failure | ||||
Oral: 2.5–10 mg every 8–12 hours Parenteral: 2.5–10 mg IM or IV every 8–12 hours | — | Used for treatment of heroin withdrawal, long-term maintenance treatment of opioid use disorder, and analgesia for chronic pain Establishment of a safe, effective dose for analgesia complicated by its long half-life (usually much longer than duration of analgesia) Requires close monitoring for several days or more after amount or frequency of dose is increased because serious toxicity can occur as the plasma level rises to steady state Risk of QT-interval prolongation; ECG monitoring recommended | ||||
Oral immediate-release: 5–30 mg every 4 hours Oral controlled-release: 15 mg every 12 hours Oral sustained-release: 30 mg every 24 hours Parenteral: 2–5 mg IV or IM every 2–4 hours as needed | > 6 months old and < 50 kg:
> 6 months old and ≥ 50 kg:
| Standard of comparison Triggers histamine release more often than other opioids, causing itching | ||||
Oral: 5–10 mg every 6 hours Oral controlled-release: 10–20 mg every 12 hours | — | |||||
Oral: 5 mg every 4 hours Oral controlled-release: 5–10 mg every 12 hours IM : 1–1.5 mg every 4 hours IV: 0.5 mg every 4 hours Rectal: 5 mg every 4–6 hours | — | May trigger less histamine release than other opioids | ||||
Opioid agonist-antagonists§ | ||||||
IV or IM: 0.3 mg every 6 hours Sublingual: 75 mcg once a day or, if tolerated, every 12 hours for ≥ 4 days, then increased to 150 mcg every 12 hours Transdermal patch: initially 5mcg/hour applied once a week; may be titrated to 20 mcg/hour once a week | Use only in patients > 13 years (same as adult dose) | Psychotomimetic effects (eg, delirium, sedation) less prominent than those of other agonist-antagonists, but other effects similar Higher affinity for mu receptors than traditional analgesics May induce acute withdrawal if added to long-term opioid therapy May be used as agonist therapy in opioid use disorder but requires special licensure | ||||
IV: Initially 1 mg, may be repeated every 3–4 hours as needed; usual range: 0.52 mg every 3–4 hours as needed IM: Initially 2 mg, may be repeated every 3–4 hours as needed; usual range: 1–4 mg every 3–4 hours as needed. Nasal: Initially1 mg (1 spray in one nostril); if adequate relief is not achieved, may be repeated in 60–90 minutes; after the second dose, may be repeated every 3–4 hours as needed | Not recommended | — | ||||
Parenteral: 10 mg IM, IV, subcutaneous every 3–6 hours | Not recommended | |||||
Pentazocine | Oral: 50–100 mg every 3–4 hours Parenteral: 30 mg IV, IM, every 3–4 hours (not to exceed 360 mg/day) | Not recommended | Usefulness limited by the following:
Can cause confusion and anxiety, especially in older patients | |||
Oral immediate-release: 50–100 mg every 4–6 hours, a second dose ≥ 1 hour later (≤ 700 mg total dose on 1st day); after 1st day, 50–100 mg every 4–6 hours (≤ 600 mg total daily dose) Oral extended-release: 50 mg every 12 hours (usual therapeutic dose of 100–250 mg every 12 hours; maximum 500 mg/day) | — | Used to treat neuropathic pain due to diabetes, moderate to severe acute pain, and moderate to severe chronic pain Reported to have fewer frequent adverse effects (eg, constipation) than other opioids, | ||||
Oral immediate-release: 50–100 mg every 4–6 hours; maximum 400 mg/day Oral extended-release: 100 mg once a day; increase by ≤ 100 mg/day every 5 days to a dose of ≤ 300 mg total daily dose | Not recommended | Less potential for abuse than with other opioids Not as potent as other opioid analgesics | ||||
* Starting doses are for opioid-naive patients. Patients with opioid tolerance or severe pain may require higher doses. | ||||||
† Not all drugs are appropriate for analgesia in children. | ||||||
§ Opioid agonist-antagonists are not usually used for chronic pain and are rarely drugs of choice for older patients. | ||||||
Opioid analgesics have proven efficacy in the treatment of acute pain, cancer pain, and pain at the end of life and as part of palliative care. Appropriate evaluation of the patient and consideration of other treatment options and the risk of opioid misuse are part of the decision-making process to balance between risk of abuse and undertreatment of pain.
Opioids are sometimes underused in patients with severe acute pain or in patients with pain and a terminal disorder such as cancer, resulting in needless pain and suffering. Reasons for undertreatment include
Underestimation of the effective dose
Overestimation of the risk of adverse effects
Generally, opioids should not be withheld when treating acute, severe pain. However, simultaneous treatment of the condition causing the pain usually limits the duration of severe pain and the need for opioids.
Generally, for acute pain, short-acting (immediate-release) pure agonist drugs are used at the lowest effective dosage possible and for a short time; Centers for Disease Control and Prevention (CDC) guidelines recommend 3 to 7 days (1). Clinicians should reevaluate patients before re-prescribing opioids. Using opioids at higher doses and/or for a longer time increases the risk of needing long-term opioid therapy, adverse effects, and opioid misuse. Patients with pain due to an acute, transient disorder (eg, fracture, burn, surgical procedure) should be switched to a nonopioid drug as soon as possible.
Generally, opioids should not be withheld when treating cancer pain; in such cases, adverse effects can be prevented or managed, and addiction is less of a concern.
There is insufficient evidence to support opioid therapy for long-term management of chronic pain due to non-terminal disorders. Also, long-term opioid therapy may result in serious adverse effects (eg, opioid use disorder [addiction], overdose, respiratory depression, death). Thus, in patients with chronic pain due to non-terminal disorders, lower-risk nonopioid therapies should be tried before opioids; these therapies include
Nonopioid drugs
Integrative (complementary and alternative) medicine techniques (eg, acupuncture, massage, transcutaneous electrical stimulation [TENS])
Cognitive-behavioral techniques
Interventional therapies (epidural injections, joint injections, nerve blocks, nerve ablation, spinal or peripheral nerve stimulation)
In patients with chronic pain due to non-terminal disorders, opioid therapy may be considered, but usually only if nonopioid therapy has been unsuccessful. In such cases, opioids are used (often in combination with nonopioid therapies) only when the benefit of pain reduction and functional improvement outweighs the risks of opioid adverse effects and misuse. Obtaining informed consent helps clarify the goals, expectations, and risks of treatment and facilitate education and counseling about misuse.
When appropriate to treat with opioids, chronic pain may be treated with long-acting formulations (see tables Opioid Analgesics and Equianalgesic Doses of Opioid Analgesics). Long-acting formulations should not be used for opioid-naive patients because they have a higher risk of serious adverse effects (eg, death due to respiratory depression).
Patients receiving long-term (> 3 months) opioid therapy should be regularly assessed for pain control, functional improvement, adverse effects, and signs of misuse. Opioid therapy should be considered a failed treatment and should be tapered and stopped if the following occur:
Patients have persistent severe pain despite increasing opioid doses.
Patients do not adhere to the terms of treatment.
Physical or mental function do not improve.
Physical dependence (development of withdrawal symptoms when a drug is stopped) should be assumed to exist in all patients treated with opioids for more than a few days. Similarly, tolerance (decreased response to the same dose of a drug that is used repeatedly) develops in all patients treated with opioids. Thus, opioids should be used as briefly as possible. In dependent patients, the dose should be tapered to control withdrawal symptoms when opioids are no longer necessary. Dependence is distinct from opioid use disorder, which typically involves compulsive use and overwhelming involvement with the drug, including craving, loss of control over use, and use despite harm. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) provides specific criteria to diagnose opioid use disorder.
To allow comparison of opioid use and risk, clinicians should consider the overall dosage of different forms as a uniform variable. The Centers for Disease Control and Prevention (CDC) structured its guidelines for opioid use and risk around the daily oral morphine
Equianalgesic Doses of Opioid Analgesics*,†
Drug | Parenteral (mg) | Oral (mg) |
|---|---|---|
2 | — | |
130 | 200 | |
1.5 | 7.5 | |
2 | 4 | |
75 | 300 | |
10 | 20 | |
10 | 30 | |
10 | — | |
15‡ | 20 | |
1 | 15 | |
Pentazocine | 60 | 180 |
| ||
† See also Kreutzwiser D, Tawfic QA and Pain Guidelines (based on Quill TE: Primer of Palliative Care, ed. 7. Chicago, Academy of Hospice and Palliative Medicine, 2019). | ||
OMME = oral morphine milligram equivalents. | ||
Route of administration
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.
Dosing and titration
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.
Adverse effects
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.
Opioid misuse, diversion, and abuse
(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
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.
Opioid analgesics references
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. 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. 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. Babu KM, Brent J, Juurlink DN: Prevention of opioid overdose. N Eng J Med 380:2246–2255, 2019. doi: 10.1056/NEJMra1807054
Adjuvant Analgesic Drugs
Drugs for Neuropathic Pain). These drugs have many uses, most notably to relieve pain with a neuropathic component.
is widely used for neuropathic pain and headache syndromes.
fibromyalgia; some evidence suggests it is effective as an anxiolytic.
For tricyclic antidepressantsserotonin and norepinephrine. Tricyclic antidepressants are effective for neuropathic pain, myofascial pain syndromes, some central neuropathic pain syndromes, visceral pain syndromes, and headache syndromes.
is a mixed mechanism (serotonin and norepinephrine) reuptake inhibitor, which appears to be effective for diabetic neuropathic pain, fibromyalgia, chronic musculoskeletal pain (including low back pain), and chemotherapy-induced neuropathy. Doses that are efficacious for depression and anxiety and for pain management are similar.
Drugs for Neuropathic Pain
Class/Drug | Dose* | Comments |
|---|---|---|
Antiseizure drugs† | ||
200–400 mg twice a day | Monitor CBC and liver function during treatment May decrease efficacy of oral contraceptives First-line treatment for trigeminal neuralgia | |
300–1200 mg 3 times a day | Starting dose usually 300 mg once a day Dosing goal: 600–1200 mg 3 times a day Adjust dose in patients with renal insufficiency | |
600–1200 mg twice a day | Starting dose usually 300 mg once a day May cause hyponatremia or decrease efficacy of oral contraceptives | |
300 mg once a day | Limited data; 2nd-line drug | |
150–300 mg twice a day Starting dose usually 75 mg twice a day, increased by the same dosage weekly as necessary to a maximum of 300 mg orally twice a day | Adjust dose in patients with renal insufficiency | |
Valproate | 250–500 mg twice a day | Limited data, but strong support for treatment of migraine |
Antidepressants | ||
10–25 mg at bedtime (starting dose), increased weekly by the same dose to a maximum of 150 mg at bedtime | Dosing goal: About 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety) Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects May increase dose to 150 mg or sometimes higher | |
10–25 mg at bedtime (starting dose), increased weekly by the same dose to maximum of 150 mg at bedtime | Dosing goal: About 100 mg/day (dosing for pain unlikely to be adequate for relieving depression or anxiety) Not recommended for older patients or patients with a heart disorder because it has strong anticholinergic effects May increase dose to 150 mg or sometimes higher | |
20–60 mg once a day (starting dose) Starting at 20–30 mg once a day and increasing by the same dosage weekly to a goal of 60 mg/day; in some cases, increasing to 60 mg twice a day (especially in patients with concomitant depression or anxiety) | Better tolerated than tricyclic antidepressants Dosing goal for pain (60 mg/day) usually sufficient to treat concomitant depression or anxiety | |
12.5 mg once a day on day 1, then increased to 12.5 mg twice a day on days 2 and 3, increased further to 25 mg twice a day on days 4 to 7, then 25 mg up to 4 times a day, not to exceed 200 mg/day | Effective for fibromyalgia; not used for neuropathic pain states | |
Extended-release (easiest to use): 37.5–75 mg once a day, increased to a target dose of 150–225 mg once a day | More norepinephrine reuptake inhibition at higher doses (≥ 150 mg/day); lower dosages ineffective for neuropathic pain Effective for pain, depression, and anxiety at this dose | |
Central alpha-2 adrenergic agonists | ||
0.1 mg once a day | Also can be used transdermally or intrathecally | |
2 mg every 6–8 hours (maximum 3 doses a day), increased by 2–4 mg every 1–4 days as needed (maximum: 36 mg a day) | ||
Corticosteroids | ||
0.5–4 mg 4 times a day | Used only for pain with an inflammatory component | |
5–60 mg once a day | Used only for pain with an inflammatory component | |
NMDA-receptor antagonists | ||
10–30 mg once a day | Limited evidence of efficacy | |
30–120 mg 4 times a day | May have a role in neuropathic pain in patients who have developed tolerance or a lower pain threshold due to central sensitization In > 90% of whites, rapid metabolism via hepatic cytochrome P-450 2D6, reducing the therapeutic effect | |
Oral sodium channel blockers | ||
150 mg once a day to 300 mg every 8 hours | Used only for neuropathic pain For patients with a significant heart disorder, cardiac evaluation recommended before the drug is started | |
Topical | ||
Apply 3 times a day | Some evidence of efficacy in neuropathic pain and arthritis | |
Up to 4 at one time† | Meaningful pain relief for 3 months after a single application | |
EMLA | Apply 3 times a day, under occlusive dressing if possible | |
Daily | Available as patch | |
Other | ||
Initially 5–10 mg 3 times a day; titrated to 60–120 mg in 3 divided doses | May act via GABA-B receptor Helpful in trigeminal neuralgia; used in other types of neuropathic pain | |
60–90 mg/month IV | Evidence of efficacy in complex regional pain syndrome | |
* Route is oral unless otherwise indicated. | ||
CBC = complete blood count; EMLA = eutectic mixture of local anesthetics; GABA = gamma-aminobutyric acid; NMDA = N-methyl-d-aspartate; WBCs = white blood cells. | ||
Neural Blockade
Interrupting nerve transmission in peripheral or central pain pathways via drugs or physical methods provides short-term and sometimes long-term relief. Neuroablation (pathway destruction) is used rarely; it is typically reserved for patients with an advanced disorder and a short life expectancy.
The most common neuroablation procedures are used to treat mechanical axial spine pain: these procedures involve radiofrequency ablation of the medial branches of the dorsal spinal root rami (which innervate zygapophyseal [facet] joints) or ablation of the lateral branches (which innervate the sacroiliac joint). This technology is also being increasingly used to treat refractory pain in the knee (genicular nerve), hip ([articular sensory] branches of the obturator and femoral nerves), and shoulder ([articular sensory] branches of the suprascapular, axillary and lateral pectoral nerves).
Neuroablation in the spinal cord has been rarely used; it is difficult to predict its effectiveness. Neuroablation of the ascending spinothalamic tract (cordotomy) can be used to disrupt pain from an area of the body (eg. whole limb); it may provide relief for several years, although numbness and dysesthesias develop. Neuroablation of the dorsal roots (rhizotomy) is used when a specific dermatome can be identified.
Neuromodulation
Stimulation of neural tissues may decrease pain, presumably by activating endogenous pain modulatory pathways. Evidence supports treatment of certain types of neuropathic pain (eg, failed back surgery syndrome with chronic leg pain after spine surgery, complex regional pain syndrome [CRPS]) using an electrode placed epidurally to stimulate the spinal cord (spinal cord stimulation).
Transcutaneous electrical nerve stimulation (TENS) uses low current at low-frequency oscillation to help manage pain.
Advances in electrical stimulation paradigms have improved the efficacy and applicability of neuromodulation techniques. Use of neuromodulation techniques in pain management has increased significantly. With the shift to limit use of opioids for nonterminal pain, neuromodulation techniques are now considered earlier as treatment options for neuropathic pain.
Advances in neuromodulation techniques and technologies include
High-frequency stimulation
Dorsal root ganglion stimulation
Burst spinal cord stimulation waveforms
Small flexible peripheral nerve stimulators
Improved MRI compatibility, which has greatly expanded the clinical situations in which neuromodulation can be used
High-frequency stimulation is efficacious for neuropathic limb pain. Efficacy is similar to that of traditional neuromodulation techniques, but evidence suggests that it may also be efficacious for axial spine pain, which is not effectively treated with traditional neuromodulation techniques.
Dorsal root ganglion stimulation is a more focused neuromodulation treatment; it targets localized neuropathic pain within limited dermatomes.
Peripheral nerve stimulation is being increasingly used to treat intractable neuropathic pain when a single peripheral nerve is involved (eg, postherniorrhaphy pain syndrome, some headache syndromes such as occipital neuralgia, meralgia paresthetica [pain in the outer part of the thigh due to compression of the lateral femoral cutaneous nerve]). It has also been used to stimulate branches of the axillary nerve to treat hemiplegic shoulder pain after stroke. Proof-of-concept studies have reported that peripheral nerve stimulation may be useful in treating postoperative pain during the first several weeks after total knee replacement, anterior cruciate ligament surgery, and foot surgery. Peripheral nerve stimulation involves inserting small, thin, flexible electrode leads percutaneously next to the affected nerve, often using ultrasound guidance. The leads are connected to a stimulator, which is fixed to the skin adjacent to the leads with a replaceable adhesive. Pain in certain areas cannot be treated with peripheral nerve stimulation because the stimulator would interfere with moving or sitting.
Stimulation of brain structures (deep brain stimulation, motor cortex stimulation) has been used for refractory neuropathic pain syndromes, but evidence is limited.
Geriatrics Essentials
In older patients, the most common causes of pain are musculoskeletal disorders. However, pain is often chronic and multifactorial, and the causes may not be clear.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Risk of ulcers and gastrointestinal (GI) bleeding due to NSAIDs for people >
The risk of cardiovascular toxicity, which occurs with nonselective NSAIDs and with coxibs, is particularly relevant to older patients, who are more likely to have cardiovascular risk factors (eg, a history of myocardial infarction (MI) or cerebrovascular or peripheral vascular disease).
Both nonselective NSAIDs and coxibs can impair renal function and cause sodium and water retention; they should be used cautiously in older patients, particularly in those who have a renal or hepatic disorder, heart failure, or hypovolemia.
Given the overall greater risk of serious toxicity in older patients, long-term NSAID therapy should be used with caution, if at all, and only for pain likely to be responsive. NSAIDS are most likely to relieve pain resulting from inflammation.
Opioids
In older patients, opioids have a longer half-life and possibly a greater analgesic effect than in younger patients. In older patients with chronic pain, short-term use of opioids appears to reduce pain and improve physical functioning but to impair cognitive function. As recognition of overdosage risks with opioids is increasing, practitioners should consider whether cognitive impairment in older patients might interfere with a patient's use of opioids and whether a caregiver can responsibly co-manage the patient's drug therapy.
Opioid-related constipation and urinary retention tend to be more problematic in older patients.
estrogen deficiency. The long-term fracture risk due to osteoporosis is a concern in older patients taking long-term opioid therapy.
