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1 July 2006

A Review of Opioid Analgesics Frequently Prescribed by Podiatric Physicians

Private practice, Shoe String Podiatry, 723 Lucerne Cir, Ormond Beach, FL 32174, USA
J. Am. Podiatr. Med. Assoc.2006, 96(4), 367-373;https://doi.org/10.7547/0960367
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Abstract

The unpleasant and subjective sensation resulting from a noxious sensory stimulus defines the phenomenon of pain. The podiatric physician is no stranger to the difficulties in achieving optimal pain therapy. Podiatric physicians must develop analgesic regimens to treat patients with acute, chronic, and postoperative pain. Because opioid therapy is the cornerstone of the pharmacologic management of acute and chronic pain, this review focuses on the prescribing of opioid analgesics to treat lower-extremity pain. The pharmacology of frequently prescribed opioids is introduced. Then, criteria for selecting appropriate opioid analgesics as found in the current medical literature are reported. Finally, a review of the literature describing legal and ethical considerations regarding the prescribing of opioid analgesics is presented.
The unpleasant and subjective sensation resulting from a noxious sensory stimulus defines the phenomenon of pain. Research has found that more than 75 million people present to a physician each year with persistent or recurrent pain [1,2]. Epidemiologic studies [3,4,5,6,7] have shown that there is an age-related increase in the prevalence of persistent pain, joint pain, and fibromyalgia among the elderly. A variety of factors may influence the severity of pain, including the underlying pathophysiology, emotional concerns, and spiritual or existential beliefs [8]. The podiatric physician is no stranger to the difficulties of achieving optimal pain therapy. Podiatric physicians must develop analgesic regimens to treat patients with acute, chronic, and postoperative pain. Analgesic opioid therapy has been the cornerstone of the pharmacologic management of acute and chronic pain. Ideally, opioid analgesics are prescribed by balancing the beneficial and adverse effects. Nist [9] presents three possible scenarios for the physician who must treat a patient in pain. First, the patient’s pain is adequately controlled until the patient makes a full recovery. In the second scenario, the physician overprescribes pain medications, resulting in an addicted patient. The third scenario is when the physician undertreats the patient’s pain. To achieve Nist’s first physician-patient scenario, the podiatric physician must become familiar with the pharmacologic properties of opioid analgesics and the legal and ethical considerations of prescribing opioid analgesics.
The central theme of this review is the prescribing of opioid analgesics to treat lower-extremity pain. First, the pharmacology of frequently prescribed opioids is introduced. Second, criteria for selecting appropriate opioid analgesics as found in the current medical literature are reported. Finally, a review of the literature describing legal and ethical considerations regarding the prescribing of opioid analgesics is presented.

Opioid Pharmacology

History
Opioids are drugs derived from opium and include morphine, codeine, and a variety of semisynthetic congeners derived from them as well as thebaine. Opium is prepared from the juice of Papaver somniferum. The milky fluid extracted from the plant’s ovary is highly narcotic after drying. This extract contains more than 20 distinct alkaloids [10]. Opium contains a variety of different substances first isolated and identified during the 19th century [10.11]. Morphine in its pure form was first extracted in 1806 by Friedrich Serturner. Codeine and papaverine followed in 1832 and 1848. Invention of the hypodermic needle in the mid-19th century led to the widespread use of morphine intravenously as an analgesic [11]. The synthetic compounds meperidine and methadone were introduced into clinical medicine just before and during World War II [10]. MacPherson [12] comments that hydromorphone, oxycodone, hydrocodone, and dihydrocodeine have all been used clinically for more than 50 years.
Opioid Receptors
Opioids interact stereospecifically with protein receptors on the membranes of certain cells in the central nervous system. Five major opioid receptor types are found in the central nervous system: Mu (μ) or OP3, Kappa (κ) or OP2, Delta (δ) or OP1, Sigma (σ), and Epsilon (ε), as well as subtypes [10,13,14]. The OP opioid receptor nomenclature is proposed by the International Union of Pharmacology system for opioid peptides. Binding potency between a particular drug and the receptor correlates with analgesia. The analgesic properties of opioids are primarily mediated by the μ (OP3) receptors. The κ (OP2) receptors found in the dorsal horn also contribute to some analgesic relief. Enkephalins interact more selectively with δ (OP1) receptors in the periphery. Activation of either κ or δ receptors seems to produce spinal analgesia [14]. The σ receptors are less specific and bind to nonopiate agents [13]. The σ receptors may be responsible for the hallucinations and dysphoria adverse events occasionally associated with opioid use [13]. The σ and ε receptors are no longer considered opioid-specific receptors because their activation does not result in analgesia [14]. All opioid receptors are coupled to inhibitory G proteins and inhibit adenylyl cyclase [13].
The five areas of the central nervous system that present with high densities of opioid receptors are the brain stem, medial thalamus, spinal cord, hypothalamus, and limbic system [13,14]. Activation of opioid receptors found in the brain stem mediates respiration, cough, nausea and vomiting, maintenance of blood pressure, pupillary diameter, and control of stomach secretions. The receptors found in the medial thalamus mediate deep pain that is poorly localized and emotionally influenced. Spinal cord receptors found in the substantia gelatinosa are involved in the receipt and integration of incoming sensory information, leading to the attenuation of painful afferent stimuli [13].
Opioids bind to peripheral sensory nerve fibers and their terminals [13]. They inhibit the Ca++-dependent release of excitatory, proinflammatory substances, such as substance P, from these nerve endings [10]. This action may contribute to the anti-inflammatory effects of opioids. Two important factors responsible for the analgesic effect of opioids are their affinity for specific receptors and their intrinsic activity at respective receptors [15]. Opioid compounds cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release.
Opioid Analgesics
Opioid analgesics are classified as agonist or antagonist drugs depending on their ability to bind or block opioid receptors [1]. Opioids each produce a wide spectrum of pharmacologic effects, including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, urinary retention, histamine release, and physical dependence [15].
Morphine, a phenanthrene, acts as a pure agonist. It binds and thus activates opioid receptors at sites in the periaqueductal and periventricular gray matter, ventromedulla, and spinal cord to produce analgesia [15]. Morphine acts at OP3 receptors in lamina I and II of the substantia gelatinosa of the spinal cord and decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also seems to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive stimuli [13]. Morphine has long been considered the gold standard of opioid agents. The pharmacokinetics of morphine vary considerably in its different formulations. Morphine dosing requirements vary with the degree of pain and a patient’s previous experience with opioids. Morphine-equivalent tables have been developed, and their purpose is to present information related to equianalgesic doses of various opioid agents compared with morphine. A table of opioid equianalgesic doses is presented here as Table 1. Intravenous doses for adults range from 2 to 10 mg per 70 kg of body weight. Prescribing of morphine to elderly patients and patients with hepatic or renal dysfunction should be approached with caution because of a higher risk of dose-related adverse effects [16].
Table 1. Adult Equianalgesic Opioid Dose Comparison.
Meperidine is a synthetic opioid known as a phenylpiperidine with a structure unrelated to morphine. It binds to OP2 opiate receptors. Meperidine does not cause pinpoint pupils but rather causes the pupils to dilate because of an atropine-like activity [13]. Meperidine is frequently administered intramuscularly. However, the intramuscular route exhibits erratic absorption and is often painful to the patient. The dosage is individualized for adults and ranges from 50 to 150 mg every 3 to 4 hours as necessary [16]. Several concerns have been reported in the literature regarding the use of meperidine. First, normeperidine is an active nonopioid metabolite that is clinically important in that it is not naloxone-reversible [15]. Normeperidine may accumulate when excessive dosing occurs or in the presence of renal failure. This may cause seizures or aggravate preexisting seizure disorders. Meperidine should not be used at doses greater than 600 mg per 24 hours or for longer than 48 hours. Finally, meperidine is not recommended for patients with impaired renal function.
Hydromorphone is a hydrogenated ketone of morphine. It is a narcotic analgesic. Hydromorphone is metabolized primarily in the liver and is excreted primarily as the glucuronide conjugate. Parenteral doses range from 1 to 2 mg subcutaneously or intramuscularly every 4 to 6 hours as needed. Severe pain may require doses of 3 to 4 mg every 4 to 6 hours as needed. If the dose needs to be given intravenously, it may be given by slow intravenous push over 2 to 3 min [16]. Hydromorphone has been implicated as a cause of transient hyperglycemia, which is a consideration if this drug is selected for a diabetic patient.
Fentanyl is a highly lipophilic synthetic opioid with a phenylpiperidine chemical structure related to meperidine. Its agonist activity occurs in the brain, spinal cord, and smooth muscle. Fentanyl is an OP3 agonist and is estimated to have 80 times the analgesic potency of morphine [10,13]. Fentanyl is indicated for its analgesic action of short duration during anesthesia and in the immediate postoperative period as needed. The maintenance low dose, infrequently needed in minor procedures, is 2 μg/kg, whereas the maintenance moderate doses range from 2 to 200 μg/kg. The podiatric physician is reminded that the respiratory depressant effect of fentanyl may persist longer than the analgesic effect. The podiatric physician may want to consider the total dose of all narcotic analgesics used. The doses of narcotics usually recommended should be reduced by one-fourth to one-third [16].
The fentanyl transdermal system is indicated for the management of chronic pain requiring continuous analgesia that cannot be managed by lesser means, such as acetaminophen-opioid combinations, nonsteroidal analgesics, or as-needed dosing with short-acting opioids. The podiatric physician must individually titrate the dose of the transdermal system to minimize the risk of adverse effects while providing analgesia. When patients are properly selected, the fentanyl transdermal system is a safe and effective alternative to other opioid regimens. To convert patients from oral or parenteral opioids to transdermal fentanyl, first calculate the previous 24-hour analgesic requirement, then convert this amount to the equianalgesic oral morphine dose using a table similar to Table 2. Most patients are adequately maintained with transdermal fentanyl administered every 72 hours. Once the system is removed, it takes 72 hours or more for the fentanyl serum concentration to decline by 50% [16].
Table 2. Initial Fentanyl Transdermal Dose Based on Daily Oral Morphine Dose.
Oxycodone is a semisynthetic opioid with a higher oral bioavailability than morphine and a half-life of 3.5 to 5 hours in its short-acting formulation. Adult dosages for the management of moderate-to-severe pain when using the immediate-release product are 10 to 30 mg every 4 hours. Controlled-release tablets are intended for the management of moderate-to-severe pain when continuous, around-the-clock analgesia is needed for an extended period. Controlled-release oxycodone has a biphasic absorption profile. The first stage involves a rapid onset, followed by a prolonged release phase. The half-life of the controlled-release formulation is 4.5 hours [16]. The controlled-release formulation allows for it to be effectively administered every 12 hours. Converting a patient from a parenteral opioid to one that may be administered by mouth is an important concept to facilitate a patient’s discharge from the institution. The data in Table 3 can be used as a guide to assist podiatric physicians in accomplishing this goal.
Table 3. Multiplication Factors for Converting the Daily Dose of Previous Opioids to the Daily Dose of Oral Oxycodone.
Propoxyphene is a derivative of methadone, to which it is structurally related. Its dextro isomer is used as an analgesic to relieve mild-to-moderate pain. Its levo isomer is not analgesic but has antitussive action [10]. The metabolite of propoxyphene known as norpropoxyphene is a proarrhythmic with a cardiac anesthetic effect similar to amitriptyline. Norpropoxyphene accumulation is associated with arrhythmias and pulmonary edema [15].
Codeine is a much less potent phenanthrene analgesic than morphine, but it has a higher oral efficacy. In contrast to morphine, codeine is approximately 60% as effective orally as parenterally, as an analgesic and as a respiratory depressant. Hepatic metabolism through the CYP-450 2D6 pathway is responsible for codeine’s metabolism to morphine [15]. Codeine shows good antitussive activity at analgesia doses. Codeine has exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine [10]. The drug has a lower abuse potential than morphine. A few opioids have a high oralparenteral potency ratio (eg, levorphanol, oxycodone, and methadone). The greater oral efficacy of these drugs is due to less first-pass metabolism in the liver [10].

Selecting an Opioid

The podiatric physician must remember that comfort is the ultimate goal when using any medication, including opioids, to manage pain. Martin [17] recently presented a comprehensive discussion on the pharmacologic management of foot pain in older patients. This discussion focuses on the selection criteria for when and how to prescribe opioids to the podiatric medical patient with pain. Before podiatric clinicians consider an opioid analgesic, they need to ensure that a complete psychosocial and physical evaluation of the patient has been performed. The term narcotic derives from the Greek word for stupor [10], and the prescribing of these drugs is regulated by state and federal agencies [18]. Opioid therapy should be prescribed appropriately to avoid undertreating patients with painful symptoms. Opioid selection is based on patient-specific factors, such as age and renal function.
Reports in the current medical compendium may be of interest to podiatric physicians who perform surgery. These sources reported that only one-fourth of the 23 million patients who underwent surgical procedures annually recalled adequate pain relief [8,19]. Beauregard et al [20] discovered that 40% of respondents to their questionnaire reported moderate-to-severe pain during the first 24 hours after hospital discharge. The pain decreased with time, but it was severe enough to interfere with their daily activities. These authors recommend aggressive analgesic treatment during a patient’s hospital stay. Also, they recommend that patients be provided with take-home analgesia protocols and comprehensive patient-education programs.
Coley et al [21] reported data on unanticipated admissions or readmissions after same-day surgery. Pain accounted for more than one-third of the return visits, incurring significant costs. These authors recommend that efforts to manage pain should not be limited to pain in the hospital but that physicians should anticipate pain-related issues before the patient’s discharge from the institution. Apfelbaum et al [22] discovered through a nationwide random telephone survey of 250 adults that additional efforts are required to improve patients’ postoperative pain experience. These authors found during their interviews that almost 25% of patients who received pain medications experienced adverse effects despite the fact that 90% of them were satisfied with their pain medications. The podiatric physician should consider these statistics when developing pain strategies for patients.
In the setting of acute pain, some podiatric clinicians become competent in the prescribing and use of a few opioid analgesics. Although no opioid seems to be superior in relieving pain, certain products are clearly inferior because of increased risks of toxic effects [8]. In some circumstances, pain control is inadequate despite dosage increases. MacPherson [12] reviews the concept of opioid rotation. This method is the replacement of the current opioid regimen with another. Analgesic equivalence is the central motif when considering opioid substitution [12]. Mercadante [23] defines the concept of opioid rotation as the substitution of another opioid for a previous one to obtain a more favorable response. Two types of opioid rotation strategies have been used: a change in opioid products or a change in the route of administration. As mentioned previously here, Table 1 provides equianalgesic doses of various opioid agents. Two limitations are apparent when reviewing the literature regarding opioid equivalence. First, despite the availability of data regarding equianalgesic doses of various opioid agents, many of these data were obtained from singledose experiments [12,24]. Second, some opioid potency studies involved different patient populations, making it difficult to draw conclusions that agree [25,26]. It is recommended that equianalgesic opioid tables be used only as a guideline for analgesia. Changes to a patient’s analgesic therapy should be based on clinical parameters. All opioids have the potential to cause nausea and vomiting, sedation, respiratory depression, and constipation [8]. No clinical comparative data have proved that equianalgesic doses of any opioid cause fewer typical adverse effects, such as nausea and constipation, than morphine [27]. Nausea and vomiting develop in approximately 10% to 40% of patients receiving opioids [8,28].
Another element of opioid analgesic therapy that the podiatric physician must consider is the route of administration. Various methods of drug delivery have been used to treat patients in pain. Standard intravenous administration may be necessary when immediate relief is required, multiple adjustments in dose are needed, or the patient cannot take oral analgesics [8]. Patient-controlled analgesia is associated with improved analgesia and patient satisfaction. The selection of a patient-controlled analgesia pump should be reserved for patients who are expected to require parenteral opioid analgesia for longer than 24 hours. An advantage of the patient-controlled analgesia pump is that it is intended to provide an individualized dosing regimen.
The intramuscular route should be avoided because it is associated with variable absorption and potential muscle necrosis, and patient acceptance is low because of injection site pain. Subcutaneous injections of morphine or hydromorphone may be an alternative route if a patient does not have intravenous access [8]. Patients should be switched to oral analgesic therapy as soon as oral intake is tolerated.

Conclusion

This review focused on the prescribing of opioid analgesics by the podiatric physician. A history of opioid therapy was presented, and the opioid pharmacology of frequently prescribed opioids was introduced as a foundation. The criteria for selecting appropriate opioid analgesics as found in the current medical literature were presented. Finally, ethical and legal considerations regarding the prescribing of opioid analgesics were described.

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