Nonintravenous Opioids

Structure-Activity

Clinically relevant nonintravenous opioids can be categorized into three structural groups: naturally occurring alkaloids, semisynthetic alkaloids, and synthetic opioids. Naturally occurring opioids can be extracted from the seeds of the poppy plant and include morphine and codeine ( Fig. 18.1 ). Although the majority of codeine available worldwide is manufactured from morphine as a semisynthetic alkaloid, codeine is found naturally along with morphine in the poppy seed. Note that codeine simply adds a methyl group on the 3-hydroxyl of morphine.

Semisynthetic alkaloids include hydromorphone (Dilaudid), hydrocodone (Norco, Vicodin), oxycodone (Percocet, Oxycontin), oxymorphone (Opana), and buprenorphine (Suboxone, Subutex). These drugs are derived from morphine, typically with substitutions of ester, hydroxyl, keto-, or methyl groups at the 3 and 6 carbon or 17 nitrogen positions of morphine ( Fig. 18.2 ).

Synthetic opioids are further characterized as phenylheptylamines, including methadone, and phenylpiperidines, including fentanyl. Tramadol and tapentadol are also included in this group. These drugs have unique chemical structures that do not follow a morphine-like pattern ( Fig. 18.3 ).

Mechanism of Action

All opioids exert their primary pharmacologic effects by interactions with opioid receptors at multiple sites in the central nervous system (CNS). The classic µ, κ, and δ opioid receptors are typical G-protein–coupled receptors (see Chapter 17 ). Binding of the opioid leads to an overall reduction in neuronal excitability via membrane hyperpolarization as the result of decreased cyclic adenosine monophosphate production, decreased calcium ion influx, and increased potassium ion efflux.

Tramadol and tapentadol are unique among nonintravenous opioids in that they bind to opioid receptors, but they also exert an analgesic effect through inhibiting reuptake of serotonin and norepinephrine; tramadol primarily inhibits serotonin reuptake and tapentadol primarily inhibits norepinephrine reuptake. Fentanyl also inhibits serotonin reuptake, although the contribution to its clinical analgesic effect is unclear.

Metabolism

The majority of nonintravenous opioids are metabolized by the cytochrome P450 system, primary via the 3A4 and 2D6 isoforms. Notable exceptions include morphine, hydromorphone, and oxymorphone. Morphine is chiefly metabolized via glucuronidation to the metabolites morphine-3-glucuronide (M3G), which has CNS neuroexcitatory effects, and morphine-6-glucuronide (M6G), an analgesic 50 times more potent than morphine. Hydromorphone and oxymorphone are the cytochrome P4502D6 metabolites of hydrocodone and oxycodone, respectively. They undergo glucuronidation as well as some reduction. Less is known about the activity of their metabolites, although hydromorphone-3-glucuronide may have CNS neuroexcitatory effects.

Most opioids are metabolized to inactive metabolites, although some, such as tramadol and codeine, are prodrugs that require metabolism to an active metabolite for clinical effect. Morphine is again a notable exception in having active metabolites. See Table 18.1 for a summary of opioid metabolism, metabolites. and their activity.

Pharmacokinetics

Opioids are unique in their availability across many routes of administration. In addition to intravenous and neuraxial administration, covered in previous chapters, they can be administered clinically by transmucosal (buccal, sublingual, or intranasal), oral, and transdermal methods. Experimental methods include inhaled opioids.

Transmucosal opioids are considered ultrashort-acting as they achieve peak plasma concentration within 10 to 20 minutes with an analgesic effect of 60 to 120 minutes. Among oral opioids there are both short-acting and extended-release formulations of multiple agents such as hydrocodone, hydromorphone, and oxycodone. There are also long-acting agents such as methadone and buprenorphine. Short-acting oral opioids allow for “as-needed” dosing for episodic or breakthrough pain and generally achieve peak plasma concentrations within 30 to 60 minutes. Extended-release formulations and long-acting agents allow for less frequent dosing and more stable analgesia in patients with constant pain as they can ameliorate large fluctuations in serum opioid levels or the so-called “peak-and-trough” effect seen with short-acting opioids. However, they differ widely in their individual pharmacokinetic properties ( Fig. 18.4 and Table 18.2 ).

Fentanyl and buprenorphine are unique because transdermal delivery systems enable continuous delivery. Modern transdermal patches use an inert polymer matrix impregnated with dissolved drug that has evolved from early transdermal systems that consisted of a simple drug reservoir separated by a rate-limiting membrane. Drug delivery with transdermal patches is a result of the concentration gradient between the patch and skin, is proportional to the area of exposed skin, and allows for a near zero-order delivery of medication at steady state without being subject to first-pass metabolism. This reduces, though does not eliminate, variability in serum opioid concentration. Additionally, this gradient is in part temperature-dependent, with increased absorption occurring at higher temperatures. Serious adverse effects and deaths have occurred with concurrent application of external heat, such as with electric heating blankets, saunas, and hot tubs.

Pharmacodynamics

Like intravenous opioids, nonintravenous opioids exert their activity through agonism of the µ-opioid receptor (see Chapter 17 ). Given their common mechanism of action, most µ-opioid receptor agonists are pharmacodynamically equivalent and produce similar effects when used in equivalent equipotent doses.

The µ-opioid agonist-antagonists are exceptions to this general rule because of their more complicated µ-receptor activity profile. Buprenorphine, the most commonly used partial agonist outside the perioperative setting, is a partial agonist at the µ receptor and an antagonist at the κ receptor. Buprenorphine exhibits a ceiling effect for analgesia and respiratory depression compared with full agonists. Tramadol has a low affinity for the µ receptor, and analgesia is only partially reversed by administration of the specific µ-receptor antagonist naloxone, presumably because of its serotonin reuptake inhibition activity. Because of this low µ-receptor affinity, the analgesia produced by tramadol might be suboptimal for severe pain.