Medication
Routes
SAO vs. LAO
Onset of action
Duration of action
PCA-availability
Fentanyl
TD, TM, IV, SC,
Both
12–24 h TD,
72 h TD,
Yes,
(Duragesic, Actiq, Fentora)
5–15 min TM
Highly variable TM
50 mcg/ml
Hydromorphone
PO
Both
15–30 min for SAO
4–6 h
Yes,
(Dilaudid, Exalgo)
IV/SC
1–3 h for LAO
24 h
1 mg/ml
Methadone
PO
LAO
30–90 min
8–12 h
No
(Dolophine)
Morphine
PO, IV, SC
Both
30–60 min SAO
3–6 h MSIR, Roxanol
Yes,
(MSIR, Roxanol, MS Contin, Kadian, Avinza)
30–90 min LAO
8–12 h MS Contin, 12–24 h, Kadian and Avinza
1 mg/ml or 5 mg/ml
Oxycodone
PO
Both
10–15 min SAO
4–6 h
No
(Roxicodone as SAO, oxycontin as LAO)
60 min LAO
8–12 h
Oxymorphone
PO
Both
(Opana, Opana ER)
Tapentadol
PO
Both
15–60 min
4–6 h
No
(Nucynta as SAO, Nucynta ER as LAO)
8–12 h Nucynta ER
Opioids are often classified as short-acting versus long-acting based on their duration of action. Formulated to provide a more rapid rise and then decrease in blood plasma levels, SAOs are considered appropriate for acute or breakthrough pain of a transient nature. The LAOs which typically last 8–72 h provide more stable plasma level concentrations over a longer period thereby avoiding the peak—trough effect of SAOs. Because the LAOs have a longer and more gradual onset of action (typically >1–2 h), they are considered to have less reward-associated reinforcement and therefore less risk of dependence. LAO agents can, however, pose an increased risk of drug accumulation and need to be titrated, monitored, and rotated carefully. Many of the oral SAO agents have been modified into longer-acting versions (see opioid table). Unlike several of its nonopioid analgesic counterparts (e.g., NSAIDs), no evidence has shown any end-organ failure from long-term use of SAOs or LAOs.
Although no opioid has been shown to be superior to the others, each compound has its own specific characteristics.
Morphine is the prototypical u– opioid agonist against which all other opioids are compared. It serves at the standard currency by which equianalgesic conversions of other opioid medications are performed. As a hydrophilic compound, it has a slower onset of action than many other opioids. Although its activity is mediated primarily by morphine’s parent molecule, morphine’s effects can be perpetuated by its two metabolites: morphine 3-glucuronide (M3G) and morphine 6-glucoronide (M6G) [31]. M3G does not possess any opioid agonist activity and is thought to be chiefly responsible for morphine’s side effects, which include generalized hyperalgesia, seizures, myoclonus, and histamine release causing pruritus. Although morphine is metabolized hepatically, both its metabolites rely on the kidneys for excretion and therefore its use must be monitored closely in patients with underlying CKD.
Oxycodone is a semisynthetic compound of morphine that is typically more potent and is associated with fewer side effects. It is metabolized by the hepatic CYP2D6 pathway into oxymorphone, the agent believed to produce its analgesic properties. Frequent abuse and misuse of this drug has resulted in a recent reformulation of the extended-release form known as oxycontin. In the estimated 10 % of patients with genetically low CYP2D6 levels, increasing doses of oxycodone or oxymorphone are not likely to produce adequate analgesia.
Hydromorphone is 5–7× more potent than morphine, but has been shown to cause less pruritus, sedation, histamine release, nausea, and emesis than morphine. Similar to morphine, hydromorphone is extensively metabolized in the liver. Its primary metabolite hydromorphone-3-glucuronide (H3G) is excreted renally and can cause neurotoxic effects (excitation syndrome: hyperalgesia, myoclonus, and epilepsy) upon accumulation.
Fentanyl, originally formulated for anesthetic purposes, has an inherently faster onset of action and is approximately 100× more potent than morphine. Its greater degree of potency compared to other opioids allow for very small amounts to be administered (micrograms versus milligrams). While primarily prescribed as a long-acting topical formulation (Duragesic) in the outpatient setting, it is also administered parentally, epidurally, and intrathecally. As a popular 72 h transdermal patch formulation, fentanyl’s effect does not require GI absorption or hepatic activation thus theoretically resulting in less GI side effects than other opioids. Because the long-lasting relief of the transdermal patches work by releasing fentanyl into body fats, many factors such as skin temperature, fat content, and proper adherence of the patch profoundly affect absorption rates.
Methadone, often best known for its role in drug addiction, has seen renewed attention in management of chronic pain due to its relatively cheap cost, high bioavailability, multiple receptor site activation, and lack of neurotoxic side effects. Though it does exert some activity at NMDA receptors which recently has been implicated in many central, chronic pain states, methadone’s unpredictable half-life (ranging from 12 to 190 h), and high interindividual pharmacokinetic variability render appropriate dosing difficult. Because the p450 pathway metabolizes it, methadone interacts with a variety of other medications. Gastric pH levels also significantly affect methadone’s degree of absorption. Methadone has also been associated with cardiac toxicity, specifically an increase of the QT interval. Therefore, a baseline EKG should be considered before starting methadone.
Despite the variety of available opioid agents, guidelines continue to recommend that opioid therapy be tailored to each patient. Analgesic responses to a drug can vary considerably due to a variety of patient factors including age and weight differences, prior opioid exposure and tolerance, and the differences in bioavailability of various opioid formulations. Recent attention to pharmacogenomics, particularly of the genetic composition of an individual’s enzymatic systems (e.g., cytochrome P450 pathway) reveals that drug metabolic rates vary widely from one patient to another. Keeping in mind such variation can certainly be helpful when selecting an appropriate analgesic agent for a patient. Although is difficult to recommend one specific molecule over others based on the data, many practitioners anecdotally report the use of fentanyl and hydromorphone in an effort to minimize cognitive and constitutional side effects.
Special Issues
Chronic opioid use is associated with a constellation of disruptive effects among the GI tract collectively known as opioid-induced bowel dysfunction (OIBD). Constipation is the most common opioid side effect, occurring in an estimated 15–90 % of patients receiving long-term opioids [23, 24]. Because a high concentration of opioid receptors reside in the gastric antrum and duodenum, opioid-induced constipation most likely occurs via a decrease in intestinal motility, and to a lesser degree, via reducing intestinal secretion [24]. Previously, the role of the mu receptor in the constipating role of opioids was identified, recent studies however have also implicated the delta receptor as playing a role [25]. Currently, there is insufficient data to suggest that one opioid agent is more likely to cause constipation than another, and unfortunately this side effect is the least likely to resolve after continued opioid use.
Other primary adverse GI affects due to opioid use include xerostomia (75 % prevalence), nausea (7–28 %), and emesis [12]. Nausea is believed to occur via stimulation of the chemoreceptor zone. Opioid agonists are shown to increase biliary duct pressure and sphincter of Oddi tone in a dose-dependent manner; however, clinical differences as a result of such have not been demonstrated. Opioid use is associated with dysfunction of nearly every part of the GI tract to some degree including the lower esophagus, the esophageal and pyloric sphincters, the stomach, small and large intestines, and even the rectum. Patients who receive long-term opioid therapy for abdominal pain (typically > 30 mg of morphine-equivalent per day) might develop narcotic bowel syndrome (NBS), characterized by chronic or frequently recurring abdominal pain that worsens with continued or escalating dosages of narcotics. Studies suggest that chronic narcotic use causes a dysregulation in the inhibitory and excitatory neural pathways resulting in visceral hyperalgesia, a state that subsequently presents its own treatment challenges [5].
The Sphincter of Oddi (SO) is a smooth muscle structure that regulates bile and pancreatic secretion flow, prevents reflux of duodenal contents into the pancreatic and biliary system, and also diverts hepatic bile into gall bladder. The Sphincter of Oddi interacts with neural and hormonal signals to reflexively contract.
Sphincter of Oddi Dysfunction (SOD) refers to two motility disorders affecting this structure: biliary dyskinesia and papillary stenosis. Of interest to pain physicians is Sphincter of Oddi dyskinesia or “spasms” caused by morphine and other opioids. The effect of opioids on the SO has long been described and in current practice, morphine is often used during biliary studies (HIDA and MRCP) to improve ductal distention.
The exact mechanism of SOD due to opioids is yet to be described; however, several hypotheses exist. It is suggested that the mechanism is not mediated via the parasympathetic system, as atropine does not appear to reverse the contractions. Naloxone has inconsistently shown to reverse opioid-induced SOD; however, this may suggest that mu or delta stimulation play a role in this reflex. Of interest, naloxone was successful in decreasing the amplitude of the phasic contractions, but showed no change in the SO basal pressure [26]. Meperidine’s ability to induce SO spasms has also promoted the opioid receptor theory [27].
Several studies have better defined the effects of opioids on the SO and provided a better understanding of this reflex. In early studies using indirect methods, investigators found that bile flow was impeded with all narcotic agents and morphine seemed to invoke the largest degree of bile duct stasis [28]. Most modern studies have employed SO manometry during ERCP to measure SO basal pressure as well as phasic contraction frequency, amplitude, and duration of contractions. At least one study with 40 subjects showed a statistically significant increase in all parameters with morphine at high doses (10 mg IM) [29]. Another study with 19 patients with normal pancreatic and biliary function showed that lower dose morphine caused increased contraction frequency, whereas at higher doses it caused increased basal pressure and contraction amplitude [26]. The findings that show morphine to be the biggest culprit of SO spasm may suggest that alternative narcotics may be a better choice for treatment of abdominal pain due to pancreatic or hepatobiliary processes. This statement however may not be completely accurate because although morphine may in fact compromise bile duct emptying; how this affects pancreatic duct emptying or the course of acute pancreatitis is not documented [28]. There is also no comparison of the outcomes in patients with acute pancreatitis treated with morphine or other narcotics. Whether SO function itself remains the same during acute pancreatitis as at baseline also remains unknown.
Related posts:
Gastroparesis: Pathophysiology of Chronic Abdominal Pain and Current Treatment
Chronic Abdominal Pain of Gynecologic Causes: Diagnosis and Treatment
Establishing Diagnosis of Chronic Abdominal Pain: Gastroenterologist View
Neurosurgical Options for Control of Chronic and Malignant Abdominal Pain
The Epidemiology of Chronic Abdominal Pain
Lessons Learned from Visceral Sensory Stimulation: Implications for Treatment of Chronic Abdominal Pain
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