Opioid Prescribing for Chronic Pain

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The following course content

Introduction   

Opioids are a class of medications used to treat chronic pain. The Centers for Disease Control and Prevention estimates that above 75% of drug overdose deaths in 2021 were from opioid medications [2]. Thus, healthcare providers must be diligent when prescribing opioids and follow best practice guidelines.  

Understanding the different pharmacokinetics, interactions, and contraindications of opioids is crucial. This course outlines opioid pharmacology and addresses pharmacokinetics, including mechanism of action, side effects, usage, and contraindications. In addition, it reviews considerations for prescribing and upcoming research regarding pain control.  

Definitions 

This section covers the definitions related to opioid medications. 

Chronic Pain: pain lasting three months or more and can be caused by any medical condition, injury, or unknown etiology [1]. 

Opioid: medication that interacts with the body’s receptors to reduce pain [1]. 

Opioid analgesics: referral to as prescription opioids [1]. 

Opioid dependence: the body physically adjusts to using opioids and when the medication is stopped, physical symptoms appear [1]. 

Opioid tolerance: the body has a reduced response to opioid medication, and thus increased dosages are required to control pain [1]. 

Opioid Overview 

This section briefly reviews opioid subclasses and the controlled substance schedules. 

Opioids are used for the treatment of chronic pain, as well as various other medical conditions in both inpatient and outpatient settings. They are divided into two major classes: full opioid agonists and atypical opioids [6]. Opioids can be classified by their mode of synthesis, which includes naturally occurring, semi-synthetic compounds, and synthetic compounds [10].  

Some examples of each are: 

• Naturally-occurring: morphine, codeine 
• Semi-synthetic: oxycodone, buprenorphine 
• Synthetic: fentanyl, methadone [10]. 

The U.S. Drug Enforcement Administration (DEA) defines and classifies mediations by schedules, ranging from I to V. Schedule I controlled substances have no acceptable medical use approved in the United States and have a high potential for abuse. Conversely, Scheduled V controlled substances have a low potential for abuse relative to schedules I through IV.  

Some examples of opioids that fall under Schedule I to III include [17]: 

• Schedule I: heroin 
• Schedule II: methadone, oxycodone 
• Schedule III: buprenorphine [17] 

Healthcare providers must follow licensure and state prescribing rules and regulations as these vary by state and professional level of practice.  

Pharmacokinetics 

This section discusses the pharmacokinetics of each opioid medication class. 

Opioids are agonists that act on specific receptor sites in the brain to control pain [9]. There are three types of opioid receptors in the central nervous system, which are mu, kappa, and delta. Opioids most commonly act on the mu-opioid receptors, but also on the delta and kappa receptors to aid in pain control and analgesia [6, 8].  

Opioid medications can be divided into two different classes, which include full opioid agonists and atypical opioids [6]. 

Full Opioid Agonists 

Full opioid agonists are a subclass of opioid medications used to control chronic pain. Examples of full opioid agonists include morphine, oxycodone, codeine, and fentanyl [6]. Morphine and Oxycodone are approved by the Federal Drug Administration (FDA) for the treatment of moderate to severe acute or chronic pain [12, 15]. Morphine is also used in an emergency setting.  

It’s administered to patients with acute coronary syndrome, as it relieves pain while also reducing the heart’s oxygen demand [12]. Codeine is often prescribed for chronic pain in patients who have cancer or are under palliative care. Off-label and non-FDA-approved indications of codeine are cough, restless leg syndrome, and persistent diarrhea [13].  

Fentanyl, a higher-potency opioid, treats severe pain in patients with advanced cancer. It has other uses, such as preoperative and postoperative analgesia, and can be used as a regional and general adjunct anesthesia [14]. 

Opioids act on both presynaptic and postsynaptic neurons. They block presynaptic calcium channels by inhibiting the release of neurotransmitters, like substance P and glutamate, which cause pain. Opioids open postsynaptic potassium channels, causing cell hyperpolarization, which inhibits cell signaling as well.  

Most full agonist opioids act at the mu receptor but can also act on the delta and kappa receptors [8]. Some opioids also can affect serotonin pathways by inhibiting serotonin reuptake or increasing the release of intrasynaptic serotonin [3]. 

Full opioid agonists are available in many forms, including sublingual, subcutaneous, intravenous (IV), oral, rectal, intramuscular (IM), and topical. Oral routes are available in immediate-release or extended-release forms. The rectal route is typically reserved for individuals who cannot take medications by mouth. Topical forms, usually Fentanyl, are administered via a transdermal patch that is removed and reapplied after a certain amount of time.  

Morphine can also be given via epidural or intrathecally through an implantable spinal pump. Recommended starting dosages of each opioid vary greatly and depend on the route, underlying pain condition being treated, and patient tolerance [3].  

Regardless of route and dosages, opioids can present potential adverse effects including: 

• Sedation 
• Central nervous system (CNS) depression 
• Nausea or vomiting 
• Constipation 
• Respiratory depression 
• Pruritis 
• Bradycardia  

[3, 8] 

Many patients prescribed opioids develop physical dependence, where they develop withdrawal symptoms when the opioid is discontinued. In addition, patients prescribed opioids for chronic pain will potentially develop a tolerance. Thus, they will likely require increased opioid dosages to feel the same effects of pain control [8].  

As some full opioid agonists affect serotonin pathways, these medications increase the likelihood of developing serotonin syndrome [3]. 

Full agonist opioids have several contraindications and therefore, healthcare providers should exercise caution when ordering these medications. Patients who have had a recent head trauma or have increased partial carbon dioxide (pCO2) from hypoventilation, or increased intracranial pressure are at increased risk for respiratory and CNS depression.  

If the patient has reduced liver or kidney function, the healthcare provider should avoid prescribing opioids when able, since they are metabolized through these organs. When prescribing any opioid, healthcare providers must be aware of the potential for opioid overdose and consider prescribing an opioid antagonist for overdose emergencies.  

Lastly, individuals with thyroid or adrenal deficiencies may be more sensitive to opioids and likely require lower dosages [8]. 

Atypical Opioids  

Atypical opioids are another subclass of opioids used to control chronic pain. Some examples of atypical opioids include buprenorphine, tramadol, and methadone [18]. Buprenorphine is FDA-approved to treat acute and chronic pain. It’s also approved to treat opioid dependence, especially for those with a heroin addiction [11].  

Tramadol is used to treat moderate to severe pain and off-label uses include treatment for premature ejaculation and restless leg syndrome [4].  

Lastly, methadone is FDA-approved to treat moderate to severe pain and for detoxification during opioid use disorder treatment. It can be used to treat neonatal abstinence syndrome, where substances were abused during pregnancy. However, this is not approved by the Federal Drug Administration [5]. 

Atypical opioids have varying mechanisms of action based on the medication and differ from full agonist opioids. Buprenorphine is a partial mu receptor agonist and a weak delta and kappa receptor agonist. It’s metabolized by the cytochrome CYP3A4 enzyme [11]. Tramadol is another partial mu receptor agonist that also inhibits the reuptake of serotonin and norepinephrine. It’s metabolized by the CYP2D6 liver enzyme, activating the M1 metabolite, which acts on the mu receptor [4].  

Methadone is a full mu receptor agonist and competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor. This medication has a longer half-life than other opioids and is 8 to 60 hours [5]. 

This subclass of opioids is available in many forms and dosages, which depend on the medication. Buprenorphine is available via transdermal patch or subcutaneous implant and in IV, IM, and sublingual routes. The dosage of buccal films and sublingual tablets starts at 75 mcg and 2mg, respectively [11]. Alternatively, tramadol is available only in oral form and immediate-release dosages start at 50mg [4].  

Methadone is available in many forms, including oral, IM, IV, epidural, and subcutaneous. Dosages depend on the route, the underlying condition being treated, and the opioid tolerance of the individual [5]. However, healthcare providers should always start at the lowest dose possible when prescribing.  

Similar to full opioid agonists, atypical opioids can pose side effects including: 

• Respiratory depression 
• CNS depression 
• Sedation 
• Nausea and vomiting 
• Dry mouth 
• Hypotension  

[4, 5, 11] 

Buprenorphine and methadone are also associated with QT prolongation [5, 11]. Atypical opioids have varying contraindications, but many are the same as full opioid agonists as described above. Buprenorphine is contraindicated in patients with suspected or confirmed gastrointestinal obstruction and has a black box warning of accidental exposure causing overdose [11].  

Healthcare providers must avoid prescribing tramadol to patients under 12 years old or patients under 18 years old who have had a tonsillectomy or adenoidectomy. Prescribing tramadol to patients who are taking monoamine oxidase inhibitors (MAOIs), or tricyclic antidepressants is contraindicated as well [4].  

Methadone has many drug interactions when compared to other atypical opioids. Therefore, healthcare providers must verify the patient’s medication list is up-to-date and accurate [5].  

Considerations for Prescribers 

This section reviews potential considerations when prescribing opioids. 

When prescribing opioids, healthcare providers must consider and review several factors. The route of administration and dosage are determined by the healthcare setting, medical condition, current medications, and patient’s tolerance level. Evidence-based treatment guidelines for prescribing opioids should be followed.  

When assessing a patient’s pain, screening tools like the Visual Analogue Scale or pain scale can help measure a patient’s pain level [8]. For patients with or undergoing opioid withdrawal, the Clinical Opiate Withdrawal (COWS) tool may also be useful. Before prescribing any opioids, healthcare providers should check the patient’s controlled-substance prescription records through the state’s Prescription Drug Monitoring Program (PDMP).  

In addition, a urine drug screen is useful for the initial assessment and monitoring of opioid medication compliance. The healthcare provider should document the necessity for prescribing opioids, medication compliance, and patient behaviors at least every three months. The patient’s age and liver and kidney function are also important factors to review before prescribing opioids [8]. 

Opioids interact with several medications and have varying adverse effects. Therefore, the healthcare provider must ensure the patient’s medication list is accurately updated. Medications like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), antifungals, and MOAIs are a few common classes of medications that pose serious interactions [3, 5, 8].  

Additionally, healthcare providers should avoid prescribing benzodiazepines to patients who are taking opioids and vice versa. Patients should be educated on the adverse effects of respiratory and CNS depression, and how alcohol can contribute to these effects when combined with opioids.  

As opioids can cause constipation, patients should understand the importance of eating a balanced, high-fiber diet and drinking adequate water when instructed by their provider. The healthcare provider should also consider prescribing stool softeners for constipation prevention [8]. 

Healthcare providers and patients should be knowledgeable about the signs of opioid overdose and withdrawal. Patients should be educated on the signs of opioid overdose, which are altered mental status, respiratory depression, and constricted pupils. When prescribing opioids, healthcare providers must consider concurrently prescribing a nonselective opioid antagonist, like naloxone, to counteract the effects of opioid overdose.  

Patients and family members should be instructed on their use [3, 8]. Alternatively, patients should also be instructed on the effects of abruptly discontinuing the use of chronic pain medications, as these can lead to withdrawal symptoms. Patients should be encouraged to report withdrawal symptoms to their healthcare provider [8]. 

Another important factor when prescribing opioids is considering alternative or adjunct treatment options. Some alternatives to opioids for pain management include nonsteroidal anti-inflammatories (NSAIDs), tricyclic antidepressants, and SNRIs. Adjunct therapies such as cognitive behavioral therapy (CBT), and physical therapy and activity are also helpful in pain control [8]. 

Upcoming Research 

This section reviews ongoing research about opioid medications. 

Over the past several years, there has been much-needed research about alternative pain management modalities to opioids. Some alternatives include those discussed above and other alternatives like nerve and spinal cord stimulators, epidural injections, and transcutaneous electric nerve stimulation [8].  

Synthetic opioids, like fentanyl, were discovered in the 1950s and extremely potent synthetic opioids, like carfentanil, were developed in the 1980s. Carfentanil is 1,000 times stronger than morphine and 50 times more than fentanyl. Therefore, it’s not widely prescribed by healthcare providers due to its high potency and risk of overdose [7].  

Nitazenes, also called benzimidazoles, are another class of opioids that is not approved for use in the United States. However, the Drug Enforcement Administration has seen an uptick in their illegal use over the past several years [16]. 

Conclusion

Opioids are approved to treat chronic pain, as well as various other conditions and off-label uses. Healthcare providers must understand the pharmacokinetics, potential adverse effects, and contraindications when selecting opioids. They should also follow current prescribing guidelines and be diligent about initially and continuously reviewing a patient’s prescription drug monitoring report, urine drug screening, list of current medications, and screening for opioid abuse and addiction. 

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