Opium and its derivatives have been described and used for analgesia for thousands of years, making it one of the oldest medicinal plants. In 3500 BC, the opium plant was often called “joy plant” by the Sumerians. Other ancient cultures also document the use of opium for treatment of pain, crying, and sleep. Morphine is the first alkaloid isolated from opium by Friedrich Wilhelm Adam Sertürner in 1817. By the 1830s, morphine became a very commonly used analgesic during the American Civil War. The use of morphine became so widespread at that time that the term “soldier disease” was used to describe those who had become dependent on morphine. Since that time, many additional derivatives have become common practice in managing acute, chronic, and terminal pain.
From 1999 to 2014, the sale of prescription opioid medications quadrupled. This increase in prescription writing has been accompanied by concordant rise in opioid use disorder (OUD), increased mortality, overdose, sexual dysfunction, fractures, myocardial infarction, constipation, and sleep-disordered breathing, leading many to question their utility and labeling this rise an epidemic, , particularly with regard to the management of chronic, nonterminal pain given lack of high-quality research examining long-term effects. It is important to note that evidence supports short-term (<12 weeks) efficacy of opioids for reducing pain and improving function in noncancer nociceptive and neuropathic pain and for the use in terminal pain management. Thus, careful patient screening and monitoring is paramount in the safe management of pain with opioid medications.
In this chapter, we will examine the pharmacology, side effects, indications, and recommendations for monitoring in the clinical setting.
Many pain modulating systems are found in the human body; the most widely studied is that of the endogenous opioid system. The first endogenous opioid, enkephalin, was discovered in 1975. Since then, several have been described, including endorphins and enkephalins ( Table 16.1 ). To date, four opioid receptor systems have been characterized at cellular, molecular, and pharmacological levels. These include the three classical receptors: μ-, κ-, and δ-, while the opioid receptor-like receptor-1 (ORL-1), cloned in 1994, represents the most recently discovered of the opioid receptor family. The International Union of Pharmacology (IUPHAR) has renamed μ, κ, δ, and ORL-1 receptors to MOR, KOP, DOP, and nociceptin opioid peptide receptor (NOP), respectively. Multiple additional subtypes within each of these receptor systems have since been proposed.
Opioid receptors are found abundantly in the central nervous system (CNS), with highest concentrations in the thalamus, the periaqueductal gray matter, and the dorsal horn of the spinal cord, as well as in peripheral organs, such as heart, lungs, liver, and gastrointestinal (GI) and reproductive tracts. Most of the spinal μ receptor binding sites are located presynaptically on the terminals of primary afferent nociceptors. It is the μ receptor that is most strongly correlated with the analgesic and addiction properties of opioid drugs. An important factor of δ and κ receptor activation is the production of spinal analgesia without concomitant respiratory depression, while the ORL-1 receptor appears to be free of abuse potential. Physiological properties of each receptor type can be seen in Table 16.2 .
|Opioid Receptor||Physiological Effect|
|Mu (μ)||Nociception, respiration, cardiovascular functions, intestinal transit, feeding, learning and memory, locomotor activity, thermoregulation, hormone secretion, immune function|
|μ 1||Supraspinal analgesia, spinal analgesia, respiratory depression, slowing of gastrointestinal motility and secretions|
|μ 2||Pruritus, nausea, vomiting, majority of cardiovascular effects, physical dependence, euphoria|
|Kappa (Κ)||Nociception, diuresis, hyperphagia, immune function, neuroendocrine function|
|Κ 1||Spinal analgesia, diuresis (via inhibition of ADH release), sedation, miosis|
|Κ 2||Minimal abuse potential for abuse, appetite|
|Κ 3||Supraspinal analgesia|
|Delta (δ)||Analgesia, motor integration, cognitive function, mood-driven behavior, gastrointestinal motility, olfaction, respiration|
|ORL-1||Instinctive and emotional behaviors, nociception|
Opioid receptors are G protein-coupled receptors and consist of an extracellular amino acid N-terminus, seven transmembrane loops, and an intracellular carboxyl C-terminus. There is significant structural homology between the three classic opioid receptors. Each receptor demonstrates a binding preference for endogenous opioids, though significant overlap does exist. The μ receptor is 66% identical to the δ receptor and 68% identical to the κ receptor and binds to endorphins more so than enkephalins. While the δ and κ receptors have 58% identical amino acid sequences, the δ receptors prefer binding to enkephalins, and the κ receptors potently bind to dynorphins. Nociceptin/orphanin FQ (N/OFQ or nociceptin) binds to the ORL-1 (NOP receptor).
Distribution, Metabolism, and Excretion
Opioid distribution is dependent on the lipophilicity of the parent compound and metabolites. The more lipophilic, the greater potential to reach the target tissue. The most lipophilic opioids are fentanyl and methadone.
Opioids differ with respect to the means by which they are metabolized, and patients differ in their ability to metabolize individual opioids. With this in mind, most opioids observe similar patterns of metabolism. The majority undergo first-pass metabolism in the liver via cytochrome enzymes, which reduces the bioavailability of the opioid (see Table 16.3 ). These enzymes promote two forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions). The purpose of this metabolism is to produce a hydrophilic drug in order to facilitate its excretion in the urine. The opioids that undergo phase 2 reaction have less potential for drug-drug interactions due to the glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase (UGT), which produces molecules that are highly hydrophilic and therefore easily excreted. Morphine, oxymorphone, tapentadol, and hydromorphone are each metabolized by phase 2 glucuronidation and are less prone to drug interactions than those eliminated using the CYP450 pathways.
|Opioid||Phase 1 Metabolism||Phase 2 Metabolism||Comments|
|Morphine||None||Glucuronidation via UGT2B7|
|Hydrocodone||CYP2D6||None||One of the metabolites of hydrocodone is hydromorphone, which undergoes phase 2 glucuronidation|
|Oxycodone||CYP3A4, CYP2D6||None||Oxycodone produces a small amount of oxymorphone, which undergoes glucuronidation|
|Methadone||CYP3A4 † , CYP2D6, CYP2B6 † , CYP2C8, CYP2C19, CYP2C9||None|
|Hydromorphone||None||Glucuronidation via UGT2B7|
|Oxymorphone||None||Glucuronidation via UGT2B7|
A byproduct of metabolism is the formation of metabolites. Metabolites produced are typically less active than the parent compound with a few exceptions. Examples are that of morphine, whose metabolite, M6G, is substantially more potent than that of morphine itself and that of codeine, in which 10% is metabolized into morphine. Additionally, some metabolites are responsible for the toxic side effects produced by opioids. The morphine metabolite, morphine-3-glucuornide (M3G), is found to have antianalgesic, allodynic, and neuroexcitatory effects. Since the majority of opioid metabolites are excreted via the kidney, accumulation and side effect risk occurs in patients with renal failure.
Due to their varied metabolism, opioids demonstrate varied absorption rates from the GI tract. Absorption is reduced as one ages, and recent literature suggests that genetic polymorphism is responsible for a varied interindividual response to the same doses of an opioid.
Certain diseases play a major role in opioid metabolism, namely liver and renal disease. Because the liver is the main site for most of opioid metabolism, hepatic impairment can significantly alter the bioavailability of an opioid and its metabolites. Liver disease, such as cirrhosis, can significantly affect opioids metabolism through the CYP450 system as well as through impaired glucuronidation. Dose reductions for most opioids may be necessary for patients with hepatic impairment. In the case of methadone, higher doses may be required to offset the lack of liver capacity to store and release methadone.
Current data indicate that in those with renal impairment, morphine and codeine administration should be used with caution due to metabolite accumulation. Oxycodone should be used with caution with careful monitoring, while hydromorphone, methadone, and fentanyl are safest ( Table 16.4 ). In those on dialysis, methadone and fentanyl are the safest opioids because they are not dialyzed and therefore do not require dose adjustments, and the major route of excretion is fecal. Fentanyl appears be the safest for short-term pain relief due to inactive metabolites. Of note, fentanyl can adsorb onto a CT 190 dialyzer membrane filter; therefore, if a CT 190 filter is used during dialysis, rotation to methadone is recommended.
|Recommendation of Use||Comment|
|Biliary excretion increases as renal excretion decreases. Methadone appears to be safe in renal failure, and no dose recommendations are necessary.|
|Well tolerated in dialysis patients; toxic metabolites may accumulate in stage 5 CKD, therefore manage conservatively.|
|Use with Caution|
|Maximum dose of 200 mg daily, associated with lower seizure threshold.|
|Should be avoided in patients in severe renal failure (GFR <30 mL/min) due to accumulation of M3G.|
|Absorption effect, distribution, and metabolism of codeine are unknown, and it has reduced excretion.|
|Oxycodone is recommended only if alternative opioids are not available. The metabolites are thought to be less neurotoxic than those of morphine and hydromorphone.|
Opioid Side Effects
Opioid use for the management of pain has received widespread scrutiny due to the high risk of abuse, misuse, addiction, and potentially fatal adverse effects. The most commonly encountered side effects include constipation, nausea, vomiting, central sedation, and respiratory suppression ( Table 16.5 ). Tolerance and physical dependency are also commonly encountered and often confused with addiction.
Constipation is the most common side effect of opioid administration. This occurs due to opioid receptors distributed throughout the tract in GI tract smooth muscle and particularly in high concentrations throughout the antrum of the stomach and the proximal small bowel. As a result, opioids inhibit relaxation of the lower esophageal sphincter, decrease propulsion of smooth muscles in the small and large intestines, increase pyloric and anal sphincter tone, delay gastric emptying, and enhance absorption of fluids from intestinal contents. This can lead to significant constipation and ileus if not properly managed .
|Opioid||Routes of administration||Equianalgesic dose (mg)||Onset of analgesia (mins)||Half life (hr)||Dose interval (h)|
|Fentanyl (mcg)||IV||0.1||1–2||2–4 h||1–2|
|Common Side Effects||Comments and Management|
|Sedation||Mostly resolves after 3–4 days. |
Consider decreasing opioid dose by 10%–25% or increasing frequency of administration with decreased dose.
May consider adding a neurostimulant (e.g., caffeine, methylphenidate).
|Constipation||Patient do not develop tolerance to this opioid effect and require prophylactic treatment. |
Begin a scheduled stimulant when opioid therapy is initiated (e.g., bisacodyl, senna).
If constipation continues with monotherapy, an osmotic laxative should be then initiated (e.g., lactulose, polyethylene glycol, milk of magnesia, magnesium citrate).
For those who do not respond to initial bowel program, consider using a peripherally acting mu-opioid receptor antagonist.
|Nausea and vomiting||Typically resolves in 3–5 days, though can reemerge with titration of opioid dose. |
Antiemetics (especially those that bind to dopaminergic receptors, such as haloperidol, metoclopramide, and prochlorperazine) are most effective.
|Less Common side effects|
|Pruritus||Due to histamine release versus neuraxial induced (less understood and challenging to treat). |
Treat with a nonsedating antihistamine (e.g., loratadine).
Consider opioid dose decrease or opioid rotation.
|Urinary retention||Reduce opioid dose by 10%–25%. |
In males, rule out postobstructive causes.
Consider opioid rotation.
|Myoclonic jerks||Often misdiagnosed and therefore under appreciated. |
Rotation to different opioid often helpful.
Benzodiazepine is the primary symptomatic treatment.
May consider baclofen.
|Rare side effects|
|Respiratory depression||Rare in chronic, stable use. More common in acute use. |
Thorough education with the patient and family members should be done prior to initiation and have a plan in place that family members can initiate if encountered.
Prescribe naloxone rescue kits that either the patient or family members are familiar with and can administer.
|Opioid allergy||Do not use the opioid that results in allergy. |
Most common are codeine, morphine, and meperidine. Codeine is the one opioid in which allergy is not uncommon.
|Opioid-induced Hyperalgesia||Most commonly seen with low dose morphine or intraoperative remifentanil. , |
Decreasing the opioid dose (40%–50%) and adding adjuvants or a low dose of methadone can be used to treat opioid-induced hyperalgesia.
Ketamine has proven effective.
Other possible treatment regimens include dextromethorphan, and nonsteroidal antiinflammatory drugs (NSAIDs), opioid switching, amantadine, buprenorphine, alpha 2 agonists, and methadone.
|Opioid||Routes of administration||MME Factor||Onset of analgesia (mins)||Half life (hr)||Dose interval (h)|
|Hydrocodone SR||Oral||1||N/A||7–9 h||12 (capsule) |
|Fentanyl||Oral-buccal or SL tablets, or lozenge/troche (mcg)||0.2–0.4||5–15 (transmucosal)||1–2|
|Fentanyl||Patch (in mcg/hr)||2.4||12–24 (h)||72|