Treatment of Pain

1. 1. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332(7553):1302-1308. doi:10.1136/bmj.332.7553.1302

2. 2. Derry CJ, Derry S, Moore RA. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. . Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain.Cochrane Database Syst Rev. 2013 Jun 24;2013(6):CD010210. doi: 10.1002/14651858.CD010210.pub2.

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 can provide stable blood levels. Modified-release oral and transdermal forms allow less frequent dosing, which is particularly important for providing overnight relief.

Certain opioids are available in other nonparenteral formulations, often for specific indications. Fentanyl, for example, is available in transmucosal and intranasal formulations for the treatment of breakthrough pain in patients with cancer. Buprenorphine comes in buccal and sublingual formulations for chronic pain as well as for the treatment of opioid use disorder as a form of opioid replacement therapy, for which subdermal formulations are available as well.Certain opioids are available in other nonparenteral formulations, often for specific indications. Fentanyl, for example, is available in transmucosal and intranasal formulations for the treatment of breakthrough pain in patients with cancer. Buprenorphine comes in buccal and sublingual formulations for chronic pain as well as for the treatment of opioid use disorder as a form of opioid replacement therapy, for which subdermal formulations are available as well.

The IV route provides the most rapid onset and thus the easiest titration, but duration of analgesia tends to be shorter. Large, rapid fluctuations in blood levels (bolus effect) can lead to toxicity at peak levels early in the dosing interval or breakthrough pain later at trough levels. Patient-controlled analgesic (PCA) systems allow patients to self-titrate dosing, and for selected patient populations (eg, certain postoperative pediatric patients or during palliative care), continuous IV infusion can be used in addition to a PCA system. PCA systems are most often used 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.

Neuraxial opioids (eg, morphine administered epidurally or intrathecally for acute pain) can provide relief, which is prolonged when a hydrophilic drug such as morphine is 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 medications (eg, local anesthetics, baclofen, ziconotide).opioids (eg, morphine administered epidurally or intrathecally for acute pain) can provide relief, which is prolonged when a hydrophilic drug such as morphine is 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 medications (eg, local anesthetics, baclofen, ziconotide).

Long-term continuous subcutaneous infusion can be used, particularly for cancer pain and in palliative care when IV access is difficult or not part of the care plan.

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 practicable 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.

Prior to initiating chronic opioid therapy, it may be beneficial to establish a maximal dose at which opioid therapy is ineffective (ie, it neither lessens pain nor leads to improvements in physical function). This is because certain adverse effects (eg, changes in hormone levels, opioid use disorder) do not present acutely and others (eg, respiratory depression, sedation, constipation, fall risk) are stochastic (ie, not always predictable). Further, escalating doses, may represent tolerance and increase the risk of physical dependence and addiction.

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.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 medication because many longer-acting opioids are given at higher doses and their adverse effects (including serious ones such as respiratory depression) last longer.

Factors such as the presence of concomitant cardiac and respiratory disease as well as the use of concomitant administration of CNS-depressants should be taken into account due to the increased risk of sedation and respiratory depression associated with opioid therapy.

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.

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, morphine 1 mg or hydromorphone 0.2 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. 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, morphine 1 mg or hydromorphone 0.2 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, morphine 0.5 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.Occasionally, a baseline infusion (eg, morphine 0.5 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.

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.

MethadoneMethadone has the highest rate of opioid-induced deaths (per prescription) of all prescribed opioids due to its QTc-prolonging effect. It should be prescribed only by professionals trained in its use. Methadone's pharmacokinetics are variable; has the highest rate of opioid-induced deaths (per prescription) of all prescribed opioids due to its QTc-prolonging effect. It should be prescribed only by professionals trained in its use. Methadone's pharmacokinetics are variable;methadone should be started at a low dose, use should be closely monitored, and dose should be increased slowly (≤ once a week) because of its long half-life, 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 medications that may affect the QT interval. Methadone is a weak antagonist of the NMDA receptor and may provide additional analgesia in addition to that provided by its agonist effect on opioid receptors. It can also provide long-term pain control in cancer and palliative care. Higher dosing of methadone is used as a form of opioid replacement therapy for those with opioid use disorder.should be used with extreme caution, if at all, in patients taking other medications that may affect the QT interval. Methadone is a weak antagonist of the NMDA receptor and may provide additional analgesia in addition to that provided by its agonist effect on opioid receptors. It can also provide long-term pain control in cancer and palliative care. Higher dosing of methadone is used as a form of opioid replacement therapy for those with opioid use disorder.

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

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, medications with a long half-life (particularly levorphanol and methadone) have a risk of delayed toxicity as plasma levels rise. Modified-release opioids typically require several days to approach steady-state levels.Because steady-state plasma levels are not approached until 4 to 5 half-lives have passed, medications with a long half-life (particularly levorphanol and methadone) 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, especially in men with benign prostatic hyperplasia.

Opioids with nonopioid mechanism of actions (eg, tramadol, meperidine, methadone) can have unique adverse effects and drug-drug interactions.  Opioids with nonopioid mechanism of actions (eg, tramadol, meperidine, methadone) can have unique adverse effects and drug-drug interactions.

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 because metabolites may accumulate and cause problems (accumulation least likely with fentanyl and methadone)because metabolites may accumulate and cause problems (accumulation least likely with fentanyl and methadone)

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 medication's effect on their ability to do these types of activities. Patients and family members should be instructed to contact one of their professionals if patients experience excessive or persistent sedation. If sedation impairs quality of life, certain stimulants may be given intermittently (eg, before a family gathering or other event that requires alertness) or, to some patients, regularly. Medications that can be effective are

• Methylphenidate Methylphenidate

• Dextroamphetamine Dextroamphetamine

• Modafinil Modafinil

Risk of overdose or respiratory depression is higher when patients

• Take other CNS depressants, such as benzodiazepines, muscle relaxants, gabapentin, and alcohol; risk is highest with benzodiazepines, which, when possible, should not be used with opioid therapyTake other CNS depressants, 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), or methadoneUse of long-acting opioids, high-dose opioids (> 100 OMME), or methadone

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

• Treating sleep apnea

• Advising patients not to drink alcohol when taking opioids

• Not prescribing benzodiazepines or other CNS depressants with opioids when possible

• Not prescribing long-acting opioids when possible

• Prescribing methadone only if trained in its unique adverse effect profilePrescribing methadone only 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)

Health care professionals should explain to patients the potential harms and benefits of any required long-term opioid therapy through an informed-consent process.

Nausea can be treated with one of the following:

• Hydroxyzine Hydroxyzine

• Metoclopramide Metoclopramide

• An antiemetic phenothiazine (eg, prochlorperazine 10 mg orally or 25 mg rectally every 6 hours)An antiemetic phenothiazine (eg, prochlorperazine 10 mg orally or 25 mg rectally every 6 hours)

• Ondansetron administered orally or intravenouslyOndansetron administered orally or intravenously

Itching is caused by histamine release and may be relieved by an antihistamine (eg, diphenhydramine 25 to 50 mg orally or IV). However, itching is also caused by direct opioid effects, which is not responsive to antihistamines and is more commonly seen with use of neuraxially administered opioids. In hospitalized patients with intractable itching caused by epidural or parenteral opioids, nalbuphine is generally more effective than diphenhydramine or hydroxyzine because it treats opioid-induced pruritus via direct mu-opioid receptor antagonism (ie, by displacing full opioid agonists and only functioning as a antagonist); in this way, it alleviates the itching without fully reversing analgesia (via kappa-opioid receptor agonism), as does naloxone (without analgesic effects found with nalbuphine).is caused by histamine release and may be relieved by an antihistamine (eg, diphenhydramine 25 to 50 mg orally or IV). However, itching is also caused by direct opioid effects, which is not responsive to antihistamines and is more commonly seen with use of neuraxially administered opioids. In hospitalized patients with intractable itching caused by epidural or parenteral opioids, nalbuphine is generally more effective than diphenhydramine or hydroxyzine because it treats opioid-induced pruritus via direct mu-opioid receptor antagonism (ie, by displacing full opioid agonists and only functioning as a antagonist); in this way, it alleviates the itching without fully reversing analgesia (via kappa-opioid receptor agonism), as does naloxone (without analgesic effects found with nalbuphine).

Constipation is common among patients who take opioids for more than a few days, and patients do not usually develop tolerance to the slowing effect on the GI tract. Preventive treatment should be considered for all patients when opioids are started, especially for predisposed patients (eg, older patients, immobile patients). Increases in dietary fiber and fluids are rarely sufficient alone, and initially, a stimulant laxative (eg, senna) and/or an osmotic laxative (eg, polyethylene glycol) should be given daily. If needed, a drug that is specific for opioid-induced constipation may also be used ((eg, senna) and/or an osmotic laxative (eg, polyethylene glycol) should be given daily. If needed, a drug that is specific for opioid-induced constipation may also be used (4). Effective drugs include

• Peripherally acting mu–opioid receptor antagonists (PAMORAs), such as naloxegol and methylnaltrexone (subcutaneously) Peripherally acting mu–opioid receptor antagonists (PAMORAs), such as naloxegol and methylnaltrexone (subcutaneously)

• Chloride channel agonists (activators), such as lubiprostone (oral) Chloride channel agonists (activators), such as lubiprostone (oral)

Both PAMORAs and chloride channel agonists can be used throughout the course of opioid therapy. The goal should be a bowel movement at least every other day with daily use of the medication; 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 with magnesium citrate, lactulose, or propylethylene glycol powder. Some patients require regular enemas.Both PAMORAs and chloride channel agonists can be used throughout the course of opioid therapy. The goal should be a bowel movement at least every other day with daily use of the medication; 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 with magnesium citrate, lactulose, or propylethylene glycol powder. Some patients require regular enemas.

For urinary retention, double voiding or using the Credé method during voiding may help; some patients benefit from adding an alpha-adrenergic blocker such as tamsulosin., double voiding or using the Credé method during voiding may help; some patients benefit from adding an alpha-adrenergic blocker such as tamsulosin.

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 can also lead to osteoporosis. Patients taking long-term opioid therapy require intermittent bone density testing.

Opioids are the leading cause of accidental death and fatal drug overdose in the United States (5). 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).

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 medication 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, Revised (DSM-5-TR) 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 (3):

• 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 psychological 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.

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 (1). 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 substance use disorder

• Family history of substance use disorder

• History of preadolescent sexual abuse

• Major psychiatric or psychological disorder (current or past)

• Younger age (< 45)

Screening tools can help identify patients at higher risk of opioid use disorder; a commonly used example is the opioid risk tool (ORT). 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 testing 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 (5, 6). Measures include

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

• Urine drug screening and testing to monitor treatment adherence (ie, to confirm that patients are taking the medications 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 a buprenorphine formulation that can be useful for analgesia and that has a ceiling effect (when not given in combination with other medications) for risk of sedation and respiratory depression. Offering buprenorphine is a useful risk-mitigation strategy because it has been shown to produce less euphoria and tolerance.Consideration of a buprenorphine formulation that can be useful for analgesia and that has a ceiling effect (when not given in combination with other medications) for risk of sedation and respiratory depression. Offering buprenorphine is a useful risk-mitigation strategy because it has been shown to produce less euphoria and tolerance.

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 with buprenorphine or methadone plus cognitive-behavioral therapies).If patients develop opioid use disorder, prescribing physicians are responsible for offering and arranging evidence-based treatment (usually drug-assisted treatment with buprenorphine or methadone plus cognitive-behavioral therapies).

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

All patients should be counseled regarding the risks of combining opioids with alcohol, anxiolytics, and other CNS-depressing medications as well as self-adjustment of dosing.

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

NaloxoneNaloxone acts in < 1 minute when given IV and slightly less rapidly when given IM. It can also be given intranasally or endotracheally. Duration of action is about 60 to 120 minutes. However, many opioids have a duration of action longer than 60 minutes; thus, repeated doses of naloxone and close monitoring are necessary. acts in naloxone and close monitoring are necessary.

The dose for acute opioid overdose 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) or an infusion can be used. If there is no response after 10 mg has been given, the diagnosis of opioid toxicity should be reconsidered.

Naloxone may precipitate withdrawal or trigger recurrent pain in patients receiving long-term opioid therapy, but in a case of life-threatening sedation or respiratory depression, naloxone therapy should be administered.Naloxone may precipitate withdrawal or trigger recurrent pain in patients receiving long-term opioid therapy, but in a case of life-threatening sedation or respiratory depression, naloxone therapy should be administered.

Naloxone is also available as a nasal spray and an auto-injector (IM). For the nasal spray, a single spray (3 mg, 4 mg, or 8 mg ) is pumped into one nostril. For the auto-injector, the dose is 2 mg injected IM or subcutaneously into the anterolateral thigh (through clothing if necessary). May repeat every 2 to 3 minutes as needed with a maximum dose of up to 10 mg total (if no response, consider alternative causes)Naloxone is also available as a nasal spray and an auto-injector (IM). For the nasal spray, a single spray (3 mg, 4 mg, or 8 mg ) is pumped into one nostril. For the auto-injector, the dose is 2 mg injected IM or subcutaneously into the anterolateral thigh (through clothing if necessary). May repeat every 2 to 3 minutes as needed with a maximum dose of up to 10 mg total (if no response, consider alternative causes)

NalmefeneNalmefene is similar to naloxone, but its duration of action is about 4 to 8 hours. Nalmefene is occasionally used to ensure prolonged opioid reversal. Its availability is limited. is similar to naloxone, but its duration of action is about 4 to 8 hours. Nalmefene is occasionally used to ensure prolonged opioid reversal. Its availability is limited.

NaltrexoneNaltrexone, an orally bioavailable opioid antagonist, is used in the treatment of opioid use disorder and alcohol use disorder and off-label for other considerations, particularly nociplastic conditions (eg, fibromyalgia). It is long-acting and generally well tolerated. Injectable naltrexone offers the advantage of not requiring daily dosing. and off-label for other considerations, particularly nociplastic conditions (eg, fibromyalgia). It is long-acting and generally well tolerated. Injectable naltrexone offers the advantage of not requiring daily dosing.

1. 1. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. Published 2022 Nov 4. doi:10.15585/mmwr.rr7103a1

2. 2. Chou R, Deyo R, Devine B, et al. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evid Rep Technol Assess (Full Rep). 2014;(218):1-219. doi:10.23970/AHRQEPCERTA218

3. 3. Diagnostic and Statistical Manual of Mental Disorders, 5th edition, Text Revision (DSM-5-TR). American Psychiatric Association Publishing, Washington, DC. pp. 608-619.

4. 4. 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

5. 5. Centers for Disease Control and Prevention. Understanding the Opioid Overdose Epidemic. November 21, 2024. Accessed January 23, 2025.

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