Minor Analgesics: Non-Opioid and Opioid Formulations

Pharmacokinetics and Pharmacodynamics

Understanding pharmacokinetics and pharmacodynamics is essential for appropriately prescribing minor opioid analgesics, interpreting related toxicology screens, and appreciating the potential mechanisms for adverse side effects. In general, medications are primarily metabolized by the cytochrome P-450 (CYP) and glucuronidation pathways. Opioid analgesics, like any medication, may be metabolized by the CYP drug-metabolizing enzyme system 2D6. Genetic polymorphism of CYP2D6 may lead to variability in enzyme breakdown and clinical effectiveness of the medication. Deficiency of CYP2D6 may be seen in whites (7%) and those of Asian descent (1%). These enzyme systems can be induced (activated) or inhibited by various agents, including drugs, alcohol, and cigarette smoke, as well as by endogenous substances. Inducers are agents that activate the CYP enzyme system and thereby lead to increased metabolism and reduced drug effect. Inhibitors may impair the CYP enzyme system and thus limit the metabolism of the drug and increase the effect of the drug. Although pharmacokinetic drug-drug interactions may affect serum levels of a drug, this may be subclinical in most patients, with significant interactions rarely occurring in vivo in only about 10%–15% of patients. Patients’ response to individual opioids may vary markedly. Recent evidence has supported more than one mechanism for µ-opioid analgesic reactions, which may be related to receptor polymorphism.

Morphine, hydromorphone, and oxymorphone are not metabolized by CYP but are metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Except for morphine and codeine, UGT enzymes metabolize medications primarily to inactive metabolites. Morphine is converted into large quantities of relatively inactive morphine-3-glucuronide (M3G) and smaller quantities of the active metabolite morphine-6-glucuronide (M6G). M6G is 50 times more potent than morphine. M3G may account for central nervous system (CNS) toxicity, including lowering of seizure thresholds. Equianalgesic oral doses of the various minor opioid combination products and morphine are listed in Table 49.3 .

Codeine

Along with morphine and thebaine, codeine (methylmorphine) is a naturally occurring opium alkaloid derivative. A weak analgesic, codeine is similar in structure to morphine but has an ­affinity for the µ-opioid receptor 300 times lower. Classically, codeine is thought to be metabolized by O -demethylation to its primary active metabolite morphine by the CYP2D6 enzyme. Studies have demonstrated that only a small percentage of the total dose (3%) is converted by CYP2D6 to morphine. Approximately 80% is directly glucuronidated by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) enzyme to codeine-6-glucuronide (C6G), an additional active metabolite. The remaining inactive metabolites are primarily norcodeine (2%) and normorphine (2.4%). Nonfunctional CYP2D6 renders codeine ineffective, perhaps because of genetic mutations or deletions or pharmacologic inhibition. Effects of codeine not related to the formation of morphine include cognitive impairment, sedation, dizziness, euphoria and dysphoria, headache, blurred vision, and prolongation of GI transit time. The average half-life of codeine is 2.5 h. Poor metabolizers, based on CYP2D6 genotypes, are present in 7%–10% of the white population and show a decreased metabolism of codeine to morphine and a diminished analgesic effect compared to normal or extensive metabolizers. Ultrarapid metabolism occurring in 1%–7% of the white population versus 3%–10% of Europeans may have an increased formation of morphine and a potential for adverse effects at recommended doses of codeine. Because of the unpredictable metabolism of codeine as an analgesic, codeine is often replaced by other opioids or combination products.

Propoxyphene (Dextropropoxyphene)

Propoxyphene (dextropropoxyphene) is a mild synthetic opioid originally synthesized in the 1950s and at one point marketed in its hydrochloride form as Darvon (65 mg; maximum, 400 mg/day), as propoxyphene napsylate (Darvocet-N 50, Darvocet-N 100), and in Europe, as co-proxamol (32.5 mg dextropropoxyphene plus 325 mg paracetamol). By the late 1960s, propoxyphene was the most widely prescribed analgesic in the United States. Reports of propoxyphene overdoses led to warnings by the United States Food and Drug Administration (FDA) in 1978 and a subsequent reduction in use. Propoxyphene’s major metabolite norpropoxyphene has fewer CNS effects than propoxyphene does but accumulates in cardiac tissue, thereby leading to a local anesthetic effect and prolongation of action potentials, in some cases fatal torsades de pointes. Because of the increasing number of fatal overdoses of co-proxamol and limited evidence supporting its efficacy versus APAP for acute and chronic pain, the British government announced the gradual withdrawal of co-proxamol from British markets in January 2005. As a result of increasing public outcry from patient advocacy groups and recommendations by an FDA advisory board group, propoxyphene was voluntarily removed from the United States market in 2011 and India in 2013. ^, It is interesting to note that at the time of its withdrawal from the market, a survey showed that 68% of pain medicine practitioners saw patients who were prescribed propoxyphene by their primary care physicians. Propoxyphene is still allowed in some countries, although with prescription.

Oxycodone

Oxycodone is a semisynthetic opioid analgesic derived from the opium alkaloid thebaine. Human studies have demonstrated it to have analgesic potency 1.5 times that of morphine after oral administration. Several active metabolites have been proposed to contribute to the clinical pharmacokinetics of oxycodone. One theory supports 3- O -demethylation by CYP2D6 to oxymorphone. Oxymorphone is a potent µ-opioid ligand with two to five times higher receptor affinity than morphine has. Though potent, oxymorphone accounts for only 10% of oxycodone metabolites. Oxymorphone has been available for several years for parenteral and rectal use and was reformulated and released in an immediate-release (IR) and extended-release (ER) schedule II formulation. In vitro studies have shown that O -demethylation of oxycodone accounts for 13% of its oxidative metabolism. Oxidation of oxycodone primarily occurs via N -demethylation by CYP3A4/5 to noroxycodone, which is the most abundant circulating metabolite in human studies. Unfortunately, noroxycodone has a weak affinity for µ-opioid receptors.

In vivo , oxycodone has potent µ-opioid receptor effects, but data suggest that the intrinsic antinociceptive effects may be additionally mediated by κ-opioid receptors. This has led some to consider oxycodone an ideal medication for opioid rotation in patients not responsive to morphine, a classic µ-opioid receptor agonist. ^, Recent studies have proposed non-CYP2D6 metabolites (noroxycodone, noroxymorphone, noroxycodols, oxycodols) as additional substances responsible for its µ-opioid receptor binding and analgesic effects. Animal studies have recently demonstrated conflicting gender-related differences in female versus male rats when examining the antinociceptive effects of oxycodone.

Hydrocodone

Hydrocodone is similar in structure to codeine but is six to eight times more potent. Hydrocodone is a prodrug and undergoes CYP2D6 metabolism to hydromorphone and CYP3A4 metabolism to noroxycodone. Hydrocodone is less potent than morphine by receptor affinity and demonstrates a relative analgesic potency of 0.59 compared to morphine. The discrepancy between hydrocodone’s binding affinity and potency versus that of morphine is possibly the result of active hydrocodone metabolites or the intrinsic efficacy of receptor activation, which is more efficient for hydrocodone than for morphine. Hydrocodone is marketed as a combination product with APAP, ibuprofen, and aspirin (HCPs).

Buprenorphine

Buprenorphine is a schedule III lipophilic semisynthetic derivative of thebaine and possesses unique opioid activity compared to ­traditional opioids, including partial μ-opioid agonist and ­multiple nonselective mixed agonist-antagonist opioid receptor activity (κ-opioid, δ-opioid), opioid receptor-like 1 [ORL1]). Buprenorphine’s unique characteristics as an opioid include a bell-shaped analgesic dose-response curve related to unique binding affinity, and ceiling effect for respiratory depression, making it an attractive option for clinical settings because of reduced potential for toxicity and overdose. The FDA indications for the use of buprenorphine include opioid detoxification, opioid maintenance treatment, and management of pain severe enough to require daily, around-the-clock, long-term opioid treatment.

Buprenorphine has multiple agonist-antagonist properties. It is a partial agonist of the μ-opioid receptor, with high binding affinity and slower dissociation from the μ-opioid receptor, which may contribute to prolonged analgesia and less potential for withdrawal. It is an antagonist of the κ-opioid and an agonist at δ-opioid receptors and also shows to have weak affinity for the ORL-1 receptor, an opioid subfamily of G protein-coupled receptors. It also possesses a strong local anesthetic effect, given that it also blocks voltage-gated sodium channels. See Figure 49.2 for a description of the unique pharmacodynamic properties of buprenorphine related to opioid receptor multi-mechanistic activity that may result in enhanced analgesia and decreased side effects.

Buprenorphine is hepatically metabolized via the CYP3A4 enzyme into norbuprenorphine and undergoes glucuronidation by UGT1A1 and UGT2B7 before being eliminated through bile excretion. The compound is thus relatively safe in those with renal compromise. Although possessing a higher degree of respiratory depression properties, the metabolite norbuprenorphine does not pass the blood–brain barrier easily and thus does not exact this side effect to the same degree as other opioid compounds. Nevertheless, respiratory depression can still be a factor to monitor.

Buprenorphine formulations include intravenous, sublingual, buccal, and transdermal systems (patch). There are two sublingual/buccal formulations of buprenorphine indicated for maintenance treatment of opioid dependence and during induction. One formulation of sublingual buprenorphine (Subutex Package Insert, Indivior UK Ltd., 2018)), available in 2 mg and 8 mg pills, is indicated for opioid dependence and is preferred for initiation of treatment. Suboxone is a combination product of buprenorphine and naloxone (Suboxone Package Insert, Indivior, Inc, 2018), formulated in a 4:1 ratio of buprenorphine to naloxone, is indicated for maintenance treatment of opioid dependence (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg, 12 mg/3 mg). Naloxone is an opioid receptor antagonist, and its addition is meant to deter abuse by crushing, which could precipitate severe opioid withdrawal.

Two buprenorphine formulations FDA approved for chronic pain include a buccal film (Belbuca) and transdermal patch (Butrans). Buprenorphine buccal film (Belbuca, Endo Pharmaceuticals, Inc, 2015) is a schedule III opioid long-acting medication indicated for chronic pain (the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate). Conversion to the buccal film from other opioids includes for those patients opioid naïve or on <30 morphine equivalent doses (MED) start at 75 mcg film every 12 h; 30–89 MED, 150 mcg every 12 h; and 90–160 MED, 300 mcg every 12 h. Incremental titrations should not be done more frequently than every four days. This medication is not indicated for patients currently on >160 MED. The dissolvable film is placed against inside the check, holding for 5 s, to allow the film to stick, and usually dissolves within 30 min. Buprenorphine buccal film includes a range of doses (75, 150, 300, 450, 600, 750, and 900 mcg). Patients being converted from other opioids should have their MED decreased to less than 30 MED prior to initiating therapy.

Buprenorphine formulated in a transdermal system or patch (Butrans Package Insert, Purdue Pharma LP 2019) provides lower serum blood levels compared to oral formulations and is indicated for chronic pain in opioid naïve and patients on relatively lower MED. This formulation is not indicated for opioid use disorder, maintenance, or detoxification.

Buprenorphine transdermal patch system (Butrans Package Insert, Purdue Pharma, 2019) provides continuous systemic delivery of buprenorphine for seven days. Dosage strengths include 5, 7.5, 10, 15, and 20 mcg/h patch systems. The product is also FDA approved for the management of pain severe enough to require around-the-clock, long-term opioid treatment and has demonstrated efficacy in chronic osteoarthritis pain and chronic low back pain. ^, For opioid naïve patients, treatment is initiated at 5 mcg/h every seven days, with dose titrating to the next higher level after a minimum of 72 h. When converting patients taking other opioids to a buprenorphine patch system, it is recommended to taper the patient’s current opioids for up to seven days to no more than 30 mg of MED before initiating therapy at 5 mcg/h for seven days. Patients on 30–80 MED can be converted with the initiation of a 10 mcg/h patch. In the United States, the maximum buprenorphine transdermal system dose is 20 mcg/h because of a potential risk of QTc interval prolongation, which was noted in clinical trials used to obtain FDA approval. Patients are advised to avoid exposing the patch site to direct external heat sources while wearing the patch because of the potential dose-dependent increase in buprenorphine release and possible opioid toxicity and overdose. The most common adverse events reported in clinical trials included nausea, dizziness, headache, and application site pruritus (Butrans Package Insert, Purdue Pharma LP 2019).

Acetaminophen

APAP (paracetamol) and APAP combination products (i.e. containing opioids) are commonly prescribed as a minor analgesic for acute and chronic pain ( Table 49.2 ). The 2000 American College of Rheumatology and similar European professional colleges have recommended it as first line pharmacologic therapy for osteoarthritis (OA). ^, Prescription APAP is available as an opioid-containing combination product (e.g. codeine, hydrocodone, oxycodone), whereas OTC preparations may be combined with pseudoephedrine or dextromethorphan as convenience drugs.

Mechanism of Action and Description

APAP (paracetamol) is a p -aminophenol analgesic that was introduced in the late 1800s in Germany, a product of the rapidly developing chemical industry. Newly synthesized compounds included synthetic antipyretics and analgesics such as acetophenetidin (phenacetin), antipyrine (phenazone), and acetylsalicylic acid (ASA; aspirin). Paracetamol, the active metabolite of phenacetin, was found to demonstrate less intense GI side effects, which led to its use as an analgesic. Paracetamol was formally introduced in the United States in the 1950s, and although it was found in the 1960s to have hepatotoxic effects with unintentional misuse and overdose, it became one of the most widely used OTC and combination prescription analgesics worldwide.

The pharmacologic mechanism of action of paracetamol remains unclear. Generally, it has known analgesic and antipyretic activity with no known peripheral anti-inflammatory or platelet effects. Its antipyretic activity may be secondary to blockade of prostaglandin (PG) production and inhibition of PG endoperoxide H ₂ synthase and COX centrally. APAP may block COX activity by reducing the active form of COX to an inactive form, but with only limited effects in the GI tract and peripherally at sites of inflammation, thus contributing to a lower GI side effect profile than that of NSAIDs. Further, recent studies have suggested that its central analgesic qualities may be related to decreased activation of a subtype of endogenous opioid peptide, β-endorphin.

APAP is available in oral and rectal formulations and is rapidly absorbed from the GI tract, mainly the small intestine. APAP has a half-life (t _½ ) of between 1.25 and 3 h and therapeutic serum levels of 10–30 µg/mL. Twenty-five percent of the dose undergoes first pass metabolism in the liver. Up to 90% of APAP is metabolized in the liver via glucuronidation and sulfate conjugation to nontoxic metabolites. The remaining 10% undergoes oxidative metabolism via the CYP system (CYP-450 2E1 and CYP-450 1A2), which is responsible for the formation of the potentially hepatotoxic and nephrotoxic metabolite N -acetyl- p -benzoquinoneimine (NAPQI; Fig. 49.3 ). This minor pathway becomes more critical when the enzyme system responsible for sulfonation and glucuronidation becomes saturated with doses higher than 150 mg/kg, thereby increasing the total fraction of NAPQI. Approximately 85% of the dose is excreted in urine within 24 h of oral dosing. NAPQI is itself detoxified by conjugation with glutathione. Case reports have suggested that clinical situations characterized by low glutathione levels (e.g. chronic hepatitis C, malnourishment, human immunodeficiency virus infection, cirrhosis) may place these patients at greater risk for adverse events from APAP. However, one study found no significant evidence that these populations are at higher risk for APAP toxicity. There are few clinically significant pharmacokinetic interactions with therapeutic doses of APAP. Although case reports have attributed an elevated international normalized ratio (INR) to APAP and oral anticoagulant drug interactions, randomized controlled studies have found no evidence of clinically significant changes in the INR. Even though studies have demonstrated an association, there is no clear evidence of cause and effect.