Introduction

Opioids and opiates together comprise a class of medications widely used primarily to control severe pain. The first-line drugs for mild to moderate acute pain treatment are acetaminophen or NSAIDs. If these first-line agents are ineffective in controlling the pain, we can use medications that target different pathways like combinations of acetaminophen and opioid. Severe acute pain is treated with potent opioids.[1] Conventionally, the term opiates refer to natural compounds usually obtained from the poppy flower base. Opioids are synthesized by chemical processes. Opiates and opioids are among the most commonly abused substances throughout the world. Addiction to opioids and opiates has become a significant health problem in the developed world since the 2000s, particularly in the United States.[2][3] About  21 to 29 percent of patients prescribed opioids for chronic pain misuse them, and about 8 and 12 percent develop an opioid use disorder. It is estimated 4 to 6 percent who misuse prescription opioids transition to heroin. Opioid overdoses accounted for more than 42,000 deaths in 2016, more than any previous year on record. About 40% of opioid overdose deaths involved a prescription opioid.[4]

Etiology

Opioids are derived synthetically from generally unrelated compounds. Opiates are derived from the liquid of the opium poppy either by direct refinement or by relatively minor chemical modifications. Both opioids and opiates act on three major classes of opioid receptors: mu, kappa, delta, and several minor classes of opioid receptors like nociceptin, and zeta. Simplifying significantly, the mu receptors are thought to provide analgesia, respiratory suppression, bradycardia, physical dependence, gastrointestinal dysmotility, and euphoria. The kappa agonism can yield hallucinations, miosis, and dysphoria. The delta receptor likely has pain control and mood modulation effects, but some have suggested that mu agonism is necessary for the delta receptor to function strongly for analgesia.[5][6] The nociceptin receptor modulates brain dopamine levels and has clinical effects like analgesia and anxiolysis. The zeta receptor, also known as the opioid growth factor receptor, can modulate certain types of cell proliferation, such as skin growths, and is not thought to have many functions in the modulation of pain or emotion.[7][8]

Epidemiology

Deaths from overdoses of opioids and opiates had substantial increases in the United States between 2000 and 2014, a pattern not seen before in history. In the early 2010s, many states in the US enacted new regulations, either enhancing scrutiny of consumers, restricting prescribers, or both. As of 2014, a marked jump in deaths from opiates, particularly heroin, was seen concurrently.[9][10] It is suggested to use the following strategies to prevent any opioid prescription diversion:

1. In patients who tend to overuse medications, it is often prudent to dispense smaller quantities of medication and see patients more frequently.
2. Pill counting is another strategy to promote adherence to the prescribed medication regimen.
3. Ordering random urine toxicology and having a written contract to clarify the conditions under which opioids will be discontinued
4. Prescription Monitoring Programs. The physician can use this program to decrease diversion by determining when a patient is receiving a prescription from multiple providers.[11]

Pathophysiology

Opioids administration can occur through a variety of routes. In the healthcare setting, the method of administration is usually intravenous, intramuscular, or oral. Different routes of administration can provide different onsets and offsets of action. In the setting of abuse, complications of problematic injection are common, diverse, and covered elsewhere (cellulitis, abscess, thrombophlebitis, endocarditis, compartment syndrome, foreign body, human immunodeficiency virus, hepatitis).[12]

Histopathology

Opioids generally do not cause any specific histopathology in and of themselves. However, there is a diversity of histopathologic changes that can occur in the presence of improper/recreational parenteral administration.

Toxicokinetics

Opioids have an extensive diversity of durations and intensities of effect. Alfentanil, for example, has a half-life of around 1.5 hours; whereas, methadone has a half-life of between 8 to 60 hours. Opioid uptake and effect can also vary by route of administration, some examples being fentanyl patches or long-acting oral formulations of oxycodone and morphine. Some, such as diphenoxylate and loperamide, have almost no effect other than suppression of bowel motility. Opioids such as methadone can significantly prolong the QT interval. Opioids can sometimes precipitate serotonin syndrome, especially when given to patients already taking a variety of psychoactive medications (antidepressant medications like SSRI). There is an evolving body of knowledge that the intensity and quality of response to opioids can vary significantly between patients, which can be unrelated to tolerance; this is likely related to genetics, but this is not well characterized at this time.[13]

History and Physical

Patients with opioid overdose typically have decreased responsiveness, hypopnea (abnormally slow respirations), slow speech, and constricted pupils. Constricted pupils may be seen in opioid tolerating individuals during active use even without the associated sedation and decreased respiratory drive issues.[14] Constipation is common, particularly in chronic consumers and the elderly. Opioids are thought to decrease bowel motility, but on occasion, bowel spasms can be produced, such as with "codeine cramps." Naloxone is the treatment of choice for opioid-induced bowel spasms. If there is intravenous use, there can be "track marks." These are very small abrasion-type skin changes overlying veins, usually in the extremities but occasionally in the neck and other anatomic locations.[15]

Evaluation

The diagnosis of acute opioid poisoning is primarily clinical. In the overdose setting, hypopnea can progress to apnea. Naloxone is a mainstay of therapy, but the practitioner must understand that first-line treatment is control of the airway and rescue breathing. Adequate intravenous access is necessary so enough fluids and medication can be administered. An initial intravenous dose of 0.4 to 0.8 mg of naloxone will quickly reverse neurologic and cardiorespiratory symptoms. In some cases, much higher doses are necessary, with case reports as high as 100 mg of naloxone required for successful resuscitation of a single overdose event (reference).[3][16][17] Bag-valve mask ventilation or similar intervention should be initiated immediately by the primary rescuer to restore oxygen supply to vital organs while other rescuers evaluate available methods of naloxone administration. Basic Life Support and Advanced Cardiac Life Support principles should be followed during the resuscitation of the opioid poisoned patient. Laboratory testing can include drug screening, but there is a widespread opinion that drug screening in this setting is not useful in making a timely diagnosis of opioid poisoning.[18] Drug screening is much more useful in screening for occult opioid use in settings such as pre-employment testing. When there is a disagreement between the patient and the provider regarding a drug screen result, gas chromatography and mass spectroscopy (GCMS) can provide a definitive answer regarding what was in the patient sample. In the United States, Medical Review Officers manage the data produced by employment drug testing.[19][20][21]

Treatment / Management

Traditional treatment of opioid/opiate addiction focuses on self-help in counseling and mentorship by individuals with opioid use disorder already successfully in recovery, focusing on drug-free living. "Drug-free" in the minds of many in recovery and treatment involves an absence of any chemicals, including those prescribed by a medical provider. In the 2010s, the concept of harm reduction became increasingly accepted by mainstream addiction treatment providers, allowing for ingested medications to be taken, with an increased focus on objective patient outcome optimization.

Chronic treatment of patients with opioid use disorder using methadone (a full mu receptor agonist), buprenorphine (a partial agonist of mu receptors and Kappa antagonist), and naltrexone (an opioid receptor antagonist) became more accepted. Increasing numbers of studies comparing various strategies of recovery and relapse suppression appeared in the literature. Concurrently, depot naltrexone injection to enhance complete opioid avoidance became available. Each naltrexone injection lasts approximately 30 days. During that time, opioids are rendered ineffective by the effect of naltrexone on the target receptors.[22][23] 

Disadvantages of naltrexone include difficulties in controlling acute pain in the setting of trauma and other acute medical issues. Depot naltrexone injection is contraindicated in the setting of chronic pain. Oral naltrexone is taken daily but is nearly always ineffective if the patient controls their dosing schedule. Observed oral naltrexone administration controlled by a significant other may have a promise, given recent literature regarding disulfiram in treating alcoholism.[24][25][3]

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota. 

Differential Diagnosis

If the classic signs of opioid toxicity are present in a comatose patient, such as constricted pupils and slow respiratory rate, assumptions are often that there is nothing else this patient could have. If after naloxone reversal, the patient appears to have normalized, this assumption can be justified. However, undifferentiated comatose patients are often seen in the emergency setting and can be challenging to evaluate and treat. Traditionally, a "coma cocktail" of 4 medications (dextrose/thiamine/naloxone/flumazenil) was used, but only one of the components of the original cocktail (naloxone) remains in use in emergency care as of early 2019.[26] Sometimes an unforeseen consequence of injecting a robust dose of naloxone into the undifferentiated comatose patient is subsequent agitation, which can at times severely limit the team's efforts to evaluate for potentially severe underlying disease unrelated to opioid toxicity. It is often best to consider a very small test dose of naloxone such as 0.4 mg intravenous in the adult patient if that medication is to be given diagnostically and to keep the differential broad regarding potential etiologies of unresponsiveness until the history and physical findings narrow that differential.

Pertinent Studies and Ongoing Trials

The proper and legal administration of in-hospital opioids are well characterized, as are the biochemical nature of the receptors involved. As of early 2019, research interests in opioid consumption focused on risk reduction in both the prevention and the subsequent management of opioid use disorder. There is growing reliance on evidence-based medicine principles in the management of opioid-tolerant patients and those with opioid substance use disorder. There is a large body of evidence at this point supporting opioid agonist management for the medication-assisted treatment of those with opioid substance use disorder.[27] However, there remains intense interest in alternative strategies such as the use of marijuana or its components, driven in large part by the stigma and lack of availability of methadone and buprenorphine management in many areas of the United States.[28] 

Some have called for the study of nation-of-origin features of heterogeneous opioid responses, noting for example that the capacity to metabolize codeine to morphine, which is several thousand times more effective for pain control per mg than codeine, is very rapid in those whose nation of origin is near the Horn of Africa. This enzymatic conversion is far slower in many White race individuals, giving these patients ineffective pain control with codeine. There are likely other variations in opioid responses that are to date poorly characterized regarding predicting which patient will have what response to which specific opioid. 

Treatment Planning

It has become increasingly apparent as of early 2019 that the duration of an outpatient opioid prescription can have a significant impact on the chance of future development of opioid use disorder. There is moderately strong evidence that there is a growing intensity of likelihood of development of opioid use disorder if outpatient opioid consumption continues longer than five days past the date of injury, with this risk intensifying as subsequent days pass and opioid consumption for the pain related to the injury has not yet ceased. Some studies suggest that NSAIDs work as well for acute pain as opioids, but others have suggested there may be confounding by genetic opioid response heterogeneity, which as this point remains poorly characterized.[29]

Toxicity and Adverse Effect Management

Patients who use opioids as prescribed can be at risk of overdose, and this risk increases sharply with concurrent consumption of outpatient benzodiazepines, even if these are also prescribed. There is a similar risk enhancement if individuals consume opioids and alcohol together.[30] There is growing evidence as of early 2019 that death risk can be significantly reduced in this population with access to home emergency naloxone reversal kits. This evidence is similar to data from studies of the heroin using population.[31] There are case reports of overdoses receiving successful rescue by lay observers with an injection of illicit buprenorphine/naloxone, but this has been unsuccessful with layperson injection of illicit buprenorphine alone.[32]

Prognosis

In the acute setting, receiving opioids for a very short duration is not likely to induce a substance use disorder. A single event of opioid toxicity likely by itself will not produce substance use disorder either. Once the opioid wears off, patients are predicted to regain normal physiology and capacity to do activities of daily living, provided the toxicity event did not result in hypoxic organ injury. Although there are claims that single doses of opioids by themselves created a cascade of disordered use, this appears to be quite rare. The more opioid doses a given patent receives, the more chance they have of expressing an opioid use disorder. 

It requires emphasis that there is a clear difference between the opioid user with prescribed, legal, controlled dosing increases in the setting of tolerance and true opioid use disorder. According to the DSM-5, to qualify as opioid use disorder, a patient must express at least some of the following features: longer consumption than expected, inability to tolerate reduced dosing, a great deal of time spent in pursuit of opioids, craving, use interferes with social obligations, use causes interpersonal problems, physically hazardous use, continued use despite pathologic consequences of use, tolerance causing a need for increased dosing for similar effects, and characteristic withdrawal state when use is reduced or stopped. The more criteria the patient has, the more likely they are to have opioid use disorder. As of early 2019, there is growing literature evidence supporting medications such as methadone or buprenorphine to stabilize opioid use disordered patients and make relapse and future opioid toxicity/overdose events less likely. Detoxification to the point of abstinence from all forms of opioids, including avoidance of such medications as buprenorphine or methadone, does not seem to provide the same relapse prevention advantage.[33][34]

Complications

Opioid overdose, if left untreated, often leads to severe permanent disability or death by hypoxic organ injury. Chronic use can lead to tolerance and risk for the development of opioid use disorder. Illicit use can lead to a variety of complications, largely related to injection, including endocarditis and all of its associated complications, abscess, cellulitis, thrombophlebitis, retained foreign bodies, compartment syndrome, human immunodeficiency virus, hepatitis, and scar formation. Body packers delivering potent opioids for the illicit market can have packets undergo enteral rupture, resulting in sudden, often catastrophic, loss of respiratory drive.[35]

Consultations

Patients who chronically consume opioids who have an opioid toxicity event are at risk for a repeat opioid toxicity event and must have proper management of that risk. Consultation with a chronic pain management doctor is advised whenever and wherever possible to optimize care, even if the primary doctor wishes to keep managing the prescription opioids. As of 2019, there has been a move away from the abrupt cessation of opioids in this setting and a move toward gradually decreased dosing until completion of the chronic pain doctor consultation to provide additional guidance to the primary care physician.

Deterrence and Patient Education

The discussion of the risk of the initial dose of outpatient oral opioids for acute pain has dramatically increased in intensity during the 2010s, particularly in pediatric and adolescent patients. Some locations in the United States mandate the written consent of the guardian of the patient before the initial outpatient opioid prescription. If there is a significant risk of misuse or overdose in the setting of chronic severe pain, some pain management doctors have found success with frequent appointments for prescriptions with very small numbers of doses. In some cases utilizing daily dosing of potent opioids to maintain the scrutiny intensity that a particular patient requires for safe consumption; for example, in the hospice patient with end-stage cancer who is actively using heroin. Many pain management doctors feel that an opioid overdose is not itself necessarily a mandate for ceasing all outpatient opioids, but it is certainly an event worth discussing at length with the patient and family regarding the risk of future overdose that this event predicts.[36] It is essential for patients consuming opioids of any kind to realize the enhanced danger opioids represent when co-ingested with substances that are GABA-ergic, such as benzodiazepines, barbiturates, or alcohol.

Enhancing Healthcare Team Outcomes

The opioids have created a major crisis in the US, with reports of dozens of people dying almost every day. To ensure patient safety, numerous guidelines have been developed to help healthcare workers mitigate the risks associated with opioid therapy. All healthcare workers who prescribe and dispense opiates are important partners in preventing the opioid overdose epidemic from getting worse. The guidelines all agree that the doses of opioids greater than 90 to 200 mg of morphine equivalents per day should be avoided. Further, when starting or switching fentanyl patches to oral opioids, the doses should be reduced by 25 to 50%. The guidelines also recommend the use of opioid risk assessment tools, written agreements, and urine drug testing to mitigate the risks.[37][38] [Level 3]

It is important for a provider to carefully evaluate for chronic pain in any patient under consideration for referral to opioid recovery services. Improper referral of chronic pain patients without proper pain control contingency can result in severe patient distress and, at times, lead to a variety of medical complications. In the 2000s and 2010s, there was a dramatic increase in population-level opioid consumption in the United States, leading to a national discussion on how to control distribution and use better. Interdiction with control of physician behavior had some modest effects in the reduction of street availability of opioids with the following results (1) a concurrent rise in consumption of heroin, and (2) no improvement in the number of overall deaths from opioids from all sources combined. Also noted was the risk of theft of medications prescribed to the elderly and disabled, and steps are in place to educate these populations regarding those risks.[11]

Portugal had a severe problem with people addicted to these drugs and overdose deaths in the 2000s and early 2010s. Shortly after regulatory changes emphasizing drug decriminalization and referral to heavily government-subsidized treatment, Portugal documented a rapid and significant drop in deaths in the substance use disordered population. Portugal's example may provide a way forward for the United States with similar policy changes.[27]

The pharmacist is perhaps in the ideal position to fight the opioid overdose epidemic. He or she should be the first to detect high prescription doses of opioids and speak to the healthcare provider before dispensing the drug. Also, the pharmacist can check the drug database to determine if the patient is a drug abuser. Thirdly the pharmacist should inform the authorities if he or she deems that a healthcare worker is overprescribing narcotics each month.[38][39] [Level 3]

Outcomes

There is good evidence to support the use of an opioid for chronic pain but only with careful monitoring and education of the patient. For all patients, nurses are in the prime position to educate patients about the potential toxicity of opioids and the risk of addiction. These interprofessional examples can be part of a coordinated plan to help stem this crisis. Data show that in the short term, education and restriction of opioid prescriptions may be helping to avert the crises, but the long-term data on whether it solves the addiction and physical dependence remain unknown.[40][41][42] [Level 5]