neurologic disorders
Treatment of Pain
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. Some opioids used for analgesia have both agonist and antagonist actions. Potential for abuse among those with a known history of abuse or addiction may be lower with agonist-antagonists (eg,buprenorphine,butorphanol) than with pure agonists (eg,morphine,oxycodone,hydromorphone), but agonist-antagonist drugs have a ceiling effect for analgesia and induce a withdrawal syndrome in patients already physically dependent on opioids. Opioid analgesics have proven efficacy in the treatment of acute pain, Pain , and 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. , 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 ( Opioid analgesics references ). 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 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. due to non-terminal disorders. Also, long-term opioid therapy may result in serious adverse effects (eg, Opioid Use Disorder and Rehabilitation [addiction], overdose, respiratory depression, death). Thus, in patients with chronic pain due to non-terminal disorders, lower-risk Nonopioid drugs Integrative (complementary and alternative) medicine techniques (eg, Acupuncture , 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 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 and Rehabilitation , 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 Opioids have different potencies based on their ability to bind to opioid receptors and the efficiency of oral absorption of the opioid versus direct injection into the vasculature. Understanding the interrelationship of these potencies is essential if patients need to be transitioned from one opioid to another or from and an oral to an IV form. For example, 30 mg of oralmorphineis equivalent to 10 mg of IVmorphine(a 3:1 oral-to-IV ratio) 20 mg of oraloxycodone 7.5 mg of oralhydromorphone To allow comparison of opioid use and risk, clinicians should consider the overall dosage of different forms as a uniform variable. TheCenters for Disease Control and Prevention (CDC)structured its guidelines for opioid use and risk around the daily oralmorphinemilligram equivalents (OMME) taken by a patient. For example, a patient taking 10 mg of oraloxycodone4 times a day is taking 40 mg of oraloxycodonea day. Based on the equianalgesic dosage conversion in the table below (20 mg oraloxycodoneequals 30 mg of oralmorphine), 40 mg of oraloxycodoneis equivalent to 60 mg of oralmorphinea day (60 mg OMME). A patient taking 4 mg of oralhydromorphone4 times a day (16 mg a day) is taking an OMME of 64 mg (from the table below); 7.5 mg of oralhydromorphoneequals 30 mg of oralmorphine(simplified to 1 mg of oralhydromorphoneequals 4 mg of oralmorphine). Theoral routefor opioids may be used for treatment of acute pain if the patient is able to tolerate oral drugs. Theoral or transdermal routeis 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)formulations offentanylare available. Lozenges are used for sedation in children and as treatment of breakthrough pain in patients who have cancer and have taken opioids before. TheIV routeprovides 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. TheIM routeprovides 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. Intraspinalopioids (eg,morphine5 to 10 mg epidurally or 0.5 to 1 mg intrathecally for acute pain) can provide relief, which is prolonged when a hydrophilic drug such asmorphineis used; they are typically used perioperatively. Implanted infusion devices can provide long-term neuraxial infusion, usually for cancer-related pain. These devices can also be used with other drugs (eg, local anesthetics,clonidine,ziconotide). Long-termcontinuous subcutaneous infusioncan 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. Nonopioid analgesics (eg,acetaminophen, NSAIDs) are often given concomitantly. Products containing both drugs are convenient, but the nonopioid may limit upward titration of the opioid dose. 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 Pain . The doses for patients with chronic noncancer pain are typically decided case by case. Patient-controlled analgesia provides a safe, flexible way to administer opioids in a hospital setting when pain is severe or oral analgesics are inadequate. The physician controls the amount and interval of the bolus and maximum dosage available over a set time interval (usually 4 hours); this maximum dose is called the lockout dosage. A bolus dose (eg,morphine1 mg orhydromorphone0.2 mg as often as every 6 minutes) is provided when patients push a button. As a safety measure, if the set time interval has not passed since the last administered dose or if the cumulative lockout dosage has been reached in the set time period, a bolus dosage is not administered when the button is pushed. Only the patient is allowed to push the administration button. If patients are sedated because of their drugs or medical condition, they are not alert enough to push the administration button, thus adding another layer of safety. Occasionally, a baseline infusion (eg,morphine0.5 to 1 mg/hour) can be considered, but if it is used with a patient-controlled bolus opioid, risk of adverse effects is higher. Thus, a baseline infusion should be used with caution in such cases, and it should be used only in patients who are alert enough to manage patient-controlled analgesia and who will use it only when needed. Patients with prior opioid exposure or with chronic pain require a higher bolus and baseline infusion dose; the available dose is further adjusted based on response. Patients with dementia cannot use patient-controlled analgesia, nor can young children; however, adolescents often can. Chronic Pain None Methadonehas the highest rate of opioid-induced deaths (per prescription) of all prescribed opioids. It should be prescribed only by practitioners trained in its use.Methadone's pharmacokinetics are variable;methadoneshould 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. Becausemethadonecan prolong the cardiac QT interval, the QTc interval should be assessed by ECG beforemethadoneinitiation and before and after any significant change inmethadonedosing.Methadoneshould 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 Because steady-state plasma levels are not approached until 4 to 5 half-lives have passed, drugs with a long half-life (particularlylevorphanolandmethadone) have a risk of delayed toxicity as plasma levels rise. Modified-release opioids typically require several days to approach steady-state levels. 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 Chronic Obstructive Pulmonary Disease (COPD) because respiratory depression is a risk Untreated Obstructive Sleep Apnea (OSA) because respiratory depression is a risk Some neurologic disorders, such as Dementia and encephalopathy, because Severe Chronic Kidney Disease because metabolites may accumulate and cause problems (accumulation least likely with Sedationis 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 Methylphenidate(5 to 10 mg orally once or twice a day, titrated by 5 mg every 3 days to a maximum dose of 40 mg a day) Dextroamphetamine(initially, 2.5 mg orally once or twice a day) Modafinil(initially, 100 mg orally for 3 to 7 days, then 200 mg orally once a day) These drugs are typically given in the morning and as needed later. The maximum dose ofmethylphenidateseldom exceeds 60 mg/day. For some patients,caffeine-containing beverages provide enough stimulation. Stimulants may also potentiate analgesia. Most patients whooverdoseor haverespiratory depressionare 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 Take other sedatives, such as benzodiazepines, muscle relaxants,gabapentin, and alcohol (risk is highest with benzodiazepines, which, when possible, should not be used with opioid therapy) 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 Use of long-acting opioids, high-dose opioids (> 100 OMME), ormethadone 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 Prescribingmethadoneonly if trained in its unique adverse effect profile Assessing the risk of overdose or serious opioid-induced respiratory depression using the Risk Index for Overdose or Serious Opioid-Induced Respiratory Depression (RIOSORD) If patients are at increased risk of overdose or respiratory depression, practitioners should discuss the risk with them and their family members and should prescribenaloxonefor them. If patients are taking long-term opioid therapy, practitioners should explain the potential harms and benefits of long-term opioid therapy through an informed consent process. Nauseacan be treated with one of the following: Hydroxyzine25 to 50 mg orally every 6 hours Metoclopramide10 to 20 mg orally every 6 hours An antiemetic phenothiazine (eg,prochlorperazine10 mg orally or 25 mg rectally every 6 hours) Ondansetron4 mg orally or IV every 8 hours Itchingis caused by histamine release and may be relieved by an antihistamine (eg,diphenhydramine25 to 50 mg orally or IV). In hospitalized patients with intractable itching caused by epidural or parenteral opioids,nalbuphine2.5 to 5 mg IV every 4 hours is generally more effective thandiphenhydramineorhydroxyzine. 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 Types of laxatives (eg, Peripherally acting mu–opioid receptor antagonists (PAMORAs), such asnaloxegol25 mg orally once a day (morning) andmethylnaltrexone(subcutaneously) 12 mg/0.6mL or 450 mg orally once a day Chloride channel agonists (activators), such aslubiprostone(oral) 24 mcg orally 2 times a day Both PAMORAs and chloride channel agonists can be used throughout the course of opioid therapy for noncancer pain. The goal should be a bowel movement at least every other day with the daily use of the drug; additional measures (eg,bisacodyl, milk of magnesia,magnesium citrate,lactulose, enema) should be used later on day 2 if no bowel movement has occurred. Persistent constipation can be managed withmagnesium citrate240 mL orally once a day,lactulose15 mL orally 2 times a day, or propylethylene glycol powder (dose is adjusted as needed). Some patients require regular enemas. 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. Forurinary retention, double voiding or using the Credé method during voiding may help; some patients benefit from adding an alpha-adrenergic blocker such astamsulosin0.4 mg orally once a day (starting dose). 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 alsoCenters 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 ( Opioid Use Disorder and Rehabilitation ) are increasing. Opioid misusemay be intentional or unintentional. It includes any use that contradicts medical advice or deviates from what is prescribed. Diversioninvolves selling or giving a prescribed drug to others. Abuserefers 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 and Rehabilitation None 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 ( Opioid analgesics references ): 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 toolscan help identify patients at higher risk of opioid use disorder; theopioid 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 Opioid analgesics references . 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 Consideration of abuprenorphineformulation that can be useful for analgesia and that has a ceiling effect on risk of sedation and respiratory depression—properties that make it an effective treatment for any opioid use disorder 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. If patients develop opioid use disorder, prescribing physicians are responsible for offering and arranging evidence-based treatment (usually drug-assisted treatment withbuprenorphineormethadoneplus cognitive-behavioral therapies). 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. Naloxoneacts 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,repeated doses ofnaloxoneand close monitoring are necessary. 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. For patients receiving long-term opioid therapy,naloxoneshould be used only to reverse respiratory depression and must be given more cautiously to avoid precipitating withdrawal or recurrent pain. Naloxoneis also available as a nasal spray and an auto-injector (IM). For the nasal spray, a single spray (2 or 4 mg in 0.1 mL) is sprayed into one nostril. For the auto-injector, the dose is 2 mg injected IM or subcutaneously into the anterolateral thigh (through clothing if necessary). Nalmefeneis similar tonaloxone, but its duration of action is about 4 to 8 hours.Nalmefeneis occasionally used to ensure prolonged opioid reversal. Naltrexone, an orally bioavailable opioid antagonist, is given as adjunctive therapy in opioid and alcohol addiction. 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