Opioid Prescribing

Mechanism of Action

[11]"Opioid" is an umbrella term that represents all compounds that bind to opioid receptors, which includes compounds derived from poppy seeds, such as morphine and codeine, as well as synthetic opioids like fentanyl. Opioid receptors are found throughout the central and peripheral nervous systems and GI tract, regulating many body functions: pain, mood, stress, reward, gastrointestinal functions, and respiration.[1][12][2]

There are three opioid receptors: mu, kappa, and delta. Mu receptors mediate most of the clinical and adverse effects of opioids: analgesia, sedation, euphoria, constipation, and respiratory distress. Activation of kappa receptors also leads to analgesia, dyspnea, and sedation. Research on the role of delta receptors is sparse.[12]

Once activated, opioid receptors start a cascade that activates G proteins and inhibits adenylyl cyclase, ultimately leading to alterations in gene transcription. Opioid receptors work on both presynaptic and postsynaptic neurons. On presynaptic neurons, opioids close voltage-gated calcium channels, leading to decreased release of pain neurotransmitters such as glutamate and substance P. This ultimately reduces transmission of pain signals. Presynaptic opioid receptors on neurons in the ventral tegmental area inhibit GABA release, causing dopaminergic neurons to fire more frequently and create feelings of euphoria. Postsynaptic opioid receptors open potassium channels, leading to cell hyperpolarization that inhibits cell signaling.[12]

Most opioids are full agonists at the mu receptor. Some, such as buprenorphine, butorphanol, and nalbuphine, are partial agonists. Tramadol, a weak opioid mu agonist, also inhibits serotonin and norepinephrine reuptake.[11][13]

Administration

Opioids come in a number of forms and can be administered orally, rectally, topically (transdermal patches), intravenously, in the epidural space, and into the dura. The mode of administration and duration of action depends on the lipophilicity and hydrophilicity of the opioid. For example, codeine can be administered via oral, intramuscular, and rectal routes. In most adults, oral codeine absorbs rapidly and reaches a peak concentration within one hour.[14]

Opioids are frequently misused. Most commonly, individuals misuse these agents in tablets or capsule dose forms. However, some abusers alter the route of administration, inhaling or injecting crushed tablets to achieve a heightened or more rapid psychoactive effect and attenuate the rewarding effect of the drug. For this reason, the Food and Drug Administration has approved abuse-deterrent formulations of opioid prescriptions to prevent the tablets from being crushed.[15][6]

Adverse Effects

Common Side Effects

• Sedation/CNS depression
• Dizziness
• Nausea
• Vomiting
• Constipation: Opioid-induced constipation is one of the most common side effects resulting from activating mu receptors in the gastrointestinal system, causing increased stool transit time. Tolerance does not occur at the mu receptors in the colon. For this reason, opioid-induced constipation does not decrease over time. Patients who use opioids long-term are encouraged to increase fluid intake, participate in regular exercise, and defecate as soon as they have the urge to void.[16][2]
• Physical dependence - Dependence often manifests with withdrawal symptoms when opioids are discontinued or decreased. Withdrawal symptoms include rhinorrhea, lacrimation, yawning, hyperventilation, hyperthermia, muscle aches, vomiting, diarrhea, and anxiety. The severity of withdrawal symptoms varies based on the chronicity of opioid intake, the type of opioid, and individual variability.[17][18][19][17]
• Tolerance - As individuals take repeated doses of opioids, they require increased medication to experience the same effect of analgesia.[2][20][2]
• Respiratory depression- Individuals with COPD, asthma, or other lung pathologies may experience fatal respiratory impairment.[3][21][3]

Uncommon Side Effects

• Hyperalgesia - Chronic use of opioids can ironically lead to hyperalgesia. 
• Delayed gastric emptying
• Muscle rigidity
• Immunologic and hormonal dysfunction
• Myoclonus 
• Cardiac arrhythmia
• Pruritis
• Xerostomia 

Narcotic bowel syndrome (NBS) occurs when individuals experience daily moderate to severe abdominal pain for three months or more. Patients may increase opioid intake to deal with the pain. Paradoxically, abdominal pain often increases in response to escalating opioid doses.[2]

Of note, if opioids are taken in intravenous form, as they often are when abused, individuals increase their risk of infections, human immunodeficiency virus, and hepatitis C virus exposure.[22] They also increase the risk of seeding bacteria on heart valves, leading to endocarditis.[23][24]

Contraindications

Opioids have relative contraindications, and each patient should have an appropriate assessment before discerning whether to administer opioids. For example, opioids are known to cause respiratory depression. Administration of opioids to patients with head trauma requires great care, as the increased pCO2 from hypoventilation can induce vasodilation and increased intracranial pressure. [25][26]  As previously noted, patients with pulmonary dysfunction may not be able to compensate for opioid-induced respiratory depression. Opioids are also not the first analgesic of choice when patients are experiencing liver or kidney dysfunction, as poor excretion and metabolism may result in the accumulation of byproducts. Individuals with adrenal and thyroid deficiencies may be more sensitive to opioids.[27]

Pregnancy is another relative contraindication as the fetus may show signs of dependency. Approximately 50% of babies develop neonatal abstinence syndrome when exposed to opioids while in the womb. Infants with neonatal abstinence syndrome may develop diarrhea, sweating, sneezing, crying, tachypnea, and irritability.[28] 

Monitoring

Clinicians often use urine drug screens for initial assessment, monitoring compliance, and documenting unusual drug behaviors when prescribing opioids. Another important tool is the Visual Analogue Scale (VAS), which measures and monitors pain levels. However, VAS has some reported issues, including whether it is a ratio or ordinal level of pain measurement. Providers who treat patients with chronic opioid therapy should incorporate prescription drug monitoring program data into the treatment protocol.[29][30]

The Clinical Opiate Withdrawal Scale (COWS) is a useful tool to evaluate individuals experiencing opioid withdrawal. Clinicians score withdrawal symptoms, including yawning, rhinorrhea, restlessness, and physiological measures, such as pulse rate, pupil size, and blood pressure to assess a patient’s level of withdrawal and infer their level of dependence on opioids.[31]

Toxicity

Naloxone, a nonselective opioid antagonist, is used to treat the central nervous system and respiratory depression associated with opioid overdose. Nearly forty years ago, the FDA approved naloxone in injectable formulations to be used by trained professionals. Due to the increase in opioid overdoses, there has been an increased momentum to distribute naloxone to individuals using opioids at a higher risk of overdose in the United States. The first program was started in Chicago in the mid-1990s and has since spread to many other cities and states. It is important to note that naloxone may precipitate withdrawal symptoms.[2][32][6]

The US FDA has approved three drugs to treat opioid dependence: methadone, buprenorphine, and naltrexone. Methadone is a long-acting mu agonist used to treat opioid withdrawal symptoms and cravings. Currently, methadone for the maintenance of narcotic addiction or detoxifying a patient is only permitted by licensed treatment programs or methadone clinics. (It can still be prescribed/dispensed for the indication of pain treatment like other opioids.) The abrupt discontinuation of methadone may result in acute withdrawal symptoms; therefore, discontinuation requires slow tapering.[17][33][17]

Buprenorphine, a long-acting partial mu agonist and kappa antagonist, reduces cravings and withdrawal symptoms. Clinicians can prescribe it with a Drug Abuse Treatment Act of 2000 waiver. Abrupt discontinuation can also result in withdrawal.[17][34][17]

Naltrexone is a mu receptor antagonist which does not require a special license or waiver for clinicians to prescribe it. Before using naltrexone to treat withdrawal or abstinence from opioids, patients must discontinue opioid use to detoxify, a potentially challenging obstacle for some patients. Naltrexone has been successful in treating alcohol, nicotine, and stimulant use disorder.[17][35][33][35]

However, research has revealed that conventional therapies like methadone or buprenorphine and naloxone do not work for all individuals with opioid use disorder, resulting in approximately 50% of patients suffering from relapse following treatment. Novel treatments, including a kappa-opioid receptor and serotonin modulator, as well as a vaccine that recruits the immune system to block opioid entry into the central nervous system, provide promising areas of research.[9]

Enhancing Healthcare Team Outcomes

To provide optimum care to individuals who may require opioid therapy, physicians should follow a multimodal and an interprofessional approach. Prescribers must work with other healthcare professionals and team up with the patient. According to the CDC's guidelines, which are supported by the FDA, a few approaches that physicians can use include:

• Limiting the prescription of opioids and beginning with short-acting opioids when necessary. Close monitoring of the patient and carefully assessing pain manifestations are imperative. The dose should be kept as low as possible, with gradual increases only to adequately manage the pain. Any requests from the patient to escalate the dose should be evaluated carefully, and the medication should be used for the shortest duration necessary. These are key objectives for the practitioner. Consulting with a pain specialist is required before starting opioid therapy in many states.[36] Patients who require longer courses of therapy for chronic pain may be started on longer-acting medications with the reduction of short-acting medications. Adjunctive treatments should be used as well to keep the dose of the opioid as low as possible for the shortest period of time.[18][37][38]
• Considering alternative treatment options for pain management, including NSAIDs for lower back pain or osteoarthritis, anticonvulsant, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants for neuropathic pain.[39][40]
• Working with a therapist or psychiatrist to provide CBT for patients dealing with chronic pain. 
• Encouraging the patient to participate in exercise therapy to improve function and reduce pain.
• Working with the pharmacist to review all of the patient's medications, provide patient education, and optimize medication safety.[40]
• Teaming with the patient to understand the patient's experiences and knowledge in overdose risk and guide patient education.
  • Vital information to obtain includes a history of overdose, history of addiction to any substance, health conditions or prescription of medication associated with respiratory depression, and renal or hepatic dysfunction. It is also essential to obtain a history of suicide attempts, as past suicide attempts and diagnosis of major depressive disorder serve as markers for an increased chance of overdose.[6]
• Discuss treatment goals and when to discontinue opioid treatment with the patient if risks begin to outweigh benefits. 
• Surveilling state drug monitoring programs. 
  • Prescribers' use of prescription drug monitoring programs and electronic databases that chronicle information regarding prescribing and dispensing controlled medications decreases diversion from patients who "doctor shop" for opioid prescriptions and may prevent overdoses. However, since prescription drug monitoring programs are voluntary in many states, use by providers is often inconsistent.[6]
• Reassessing opioid therapy use and risks and benefits every three months. Often, prescribers obtain urine drug screens as they monitor patients on chronic opioid therapy. 
• Providing the patient with evidence-based treatment, such as methadone or buprenorphine, if they present with opioid use disorder.[41]

The most common form of diversion for prescription opioids includes patients providing medication to family members or friends attempting to self-medicate for pain. To combat this issue, prescribers must educate patients on the dangers of sharing medication and the importance of safely storing and disposing of medication.[6]

The FDA also requires pharmaceutical companies who manufacture opioids to develop a training program that would teach prescribers how to decide which patients require opioid therapy, dose and monitor medication, and educate patients on safe use, disposal, and storage of the medication. Companies are also required to provide patient education sheets that physicians can provide to patients on opioid therapy. Moreover, in July of 2019, the FDA adopted a drug safety program called Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids in hopes of decreasing the risks from inappropriate prescribing and abuse of opioids while allowing patients who need opioid therapy to get the treatment they deserve.[42][43]

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. 

Therapeutic opioid therapy requires the efforts and surveillance of the entire interdisciplinary healthcare team. Clinicians must follow the concepts outlined above when prescribing these agents. Nurses should counsel patients and be vigilant for signs of "drug-seeking" behavior, informing the prescriber of any concerns. The pharmacist may be in the best position to spot potential misuse since their position serves as the distribution point for the drug; it may be possible to notice "doctor shopping" behavior and report such to the prescribers. All members need to collaborate in these efforts, ensuring that those patients who actually need and can benefit from opioid therapy get the treatment they need and deserve. [Level 5]