Practical Guide to the Management of Acute and Chronic Pain in the Presence of Drug Tolerance for the Healthcare Practitioner

Cocaine

Cocaine is a derivate of the coca alkaloid that is present in the leafy extract of the shrub Erythroxylon coca native to South America. Adding water and ammonia or baking soda and then heating coca converts it to the alkalinized form known as cocaine. The purity of cocaine derived by this method of extraction can be as high as 95% with bioavailability of approximately 80% via the inhalation or intranasal routes and 30% via oral ingestion.³ The onset of cocaine's euphoric effects occur at 3 minutes with intravenous administration, at 15 minutes with intranasal administration, and at 20 minutes with oral administration. Cocaine is metabolized by the liver and plasma cholinesterases to metabolites that are excreted via the kidneys. Common signs and symptoms seen in acute exposures and chronic abuse/overdose of cocaine are listed in Table 1.

Amphetamines and Designer Drugs

Amphetamines, also known as poor man's cocaine, are not strictly illicit if used correctly. However, this class of drug is often abused and can quickly result in an addiction. Amphetamines stimulate the central nervous system and cause euphoria, personality changes such as aggression, and increased alertness. The routes of use include inhalation, intravenous, and oral. The mechanism of action of amphetamine is by sympathetic stimulation through the release of serotonin, dopamine, and noradrenaline.⁴ Only about 70% of the drug is metabolized; the rest is excreted unchanged via the kidneys. Urine testing can detect an amphetamine several days after its last use because of its variable half-life.

Federally controlled substances altered to produce special effects and bypass legal regulations are termed designer drugs. The most commonly used designer drug is Ecstasy—3,4 methylenedioxymethamphetamine—also called MDMA. Ecstasy is both a stimulant and a hallucinogen, and its effects last from 3 hours to several days. Common signs and symptoms seen in acute exposures and chronic abuse/overdose of MDMA are listed in Table 2.

Hallucinogens

The hallucinogens class includes lysergic acid diethylamide (LSD), mescaline, phencyclidine (PCP), and psilocybin. These drugs cause tolerance and psychological drug dependence but not physical drug dependence or withdrawal.

LSD is an odorless and colorless substance obtained from a rye fungus and the seeds of the morning glory plant. It is semisynthetic and produces psychedelic effects such as distortion of time and perceptions of colored visual patterns and abnormal movements. Psychological effects include dysphoria, euphoria, and changes in emotion and moods.⁵ LSD also causes multiple physical effects including dilation of the pupils, salivation, dry mouth, loss of appetite, nausea, blurred vision, perspiration, hyperglycemia, hypertension, tachycardia, and hyperthermia. The mechanism of action of LSD is thought to be predominantly by serotonin neurotransporter interactions. Hallucinogen persisting perception disorder, also known as flashbacks, and psychosis are 2 long-term effects that can be exacerbated by other drugs such as sertraline, fluoxetine, and marijuana.

PCP, also known as angel dust, was initially used as an anesthetic, but that use was discontinued because of the drug's intense psychiatric effects: disorientation, agitation, delirium, and hallucination.³ PCP and its derivatives also produce the phenomenon of dissociation. The mechanism of action of dissociation is thought to result from antagonist, partial agonist, and agonist effects at various receptors, including the serotonin, adrenergic, and dopaminergic receptors. The dissociation usually lasts for about 10 hours after an onset 1 to 2 hours after oral ingestion of the drug. Ketamine, the most well-known PCP derivative, has analgesic, anesthetic, sedative, and amnesic properties.⁶ Ketamine activates the sympathetic system, causing myriad effects such as delirium, depression, amnesia, cognitive dysfunction, and dysfunction in long-term memory. Ketamine has N methyl aspartate (NMDA) blocking effects that are important for the treatment of chronic pain in which the NMDA receptors are often activated. Common signs and symptoms seen in acute exposures and chronic abuse/overdose of hallucinogens are listed in Table 3.

Marijuana

Marijuana, a hallucinogen extracted from the dried leaves of the Cannabis sativa plant, is the most commonly abused illicit substance in the United States.^6,7 The active ingredient in marijuana, tetrahydrocannabinol (THC), has psychoactive properties. The drug is most commonly inhaled although it can also be taken orally. Euphoric effects start within minutes and usually subside within 2-3 hours. THC has a relatively long half-life of up to a week, possibly because of its high lipid solubility. Tachycardia, anxiety, and congestion of the conjunctiva are some of the drug's common side effects, and hallucinations, fear, delusions, violent behavior, and depression are some of its adverse effects. Abrupt cessation after chronic use can lead to withdrawal effects manifested by mood alterations and insomnia. Effects associated with chronic use are confusion, shortened memory span, cognitive impairment, dulling of reflexes, and altered perception of time. Because marijuana has both stimulatory and sedative effects, concomitant use of substances such benzodiazepines and alcohol can augment its sedative effects, while the use of substances such as amphetamines and cocaine can augment its stimulatory effects.⁸

Methadone and Heroin

Commonly abused opioids include heroin and methadone. The cost to the US healthcare system of heroin addiction has been estimated to be $22 billion, and the number of heroin users in the US in 1996 was estimated to be 980,000.⁹ An increase in the incidence of heroin abuse among pregnant patients was reported in 2003.¹⁰ Common signs and symptoms seen in acute exposures and chronic abuse/overdoses of opioids are listed in Table 4.

Prescription Drugs

Prescription drug abuse with opioids, nonopioid pain relievers, and sedatives and tranquilizers that are often used as adjuncts to pain medications is on the rise.⁷ Commonly abused prescription opioids are oxycodone, morphine, codeine, pentazocine, propoxyphene, and fentanyl. Chronic opioid abuse leads to physical dependence, and its cessation leads to withdrawal. Tolerance and physical dependence may be produced by effects at the locus coeruleus by upregulation of the cyclic monophosphate pathway.

Interpretation of Urine Drug Tests

Practitioners must be familiar with urine screening and interpret the qualitative tests appropriately. Drug interactions must be considered in any interpretation of screening results.

Use of a single opioid can result in more than 1 metabolite, the metabolic product might itself be another opioid, and multiple opioids could be metabolized to the same opioid, leading to challenges in interpretation. For example, patients using morphine, codeine, and heroin could all test positive for the presence of morphine because morphine, codeine, and heroin all metabolize to morphine. A false positive test for hydromorphone can occur when hydrocodone is taken. False negative results can be seen with rapid metabolizers; heroin has a half-life of 30 minutes and the metabolite acetylmorphine has a half-life of 45 minutes. Urine testing is useful when performed 2-4 days after the use of a drug,²⁹ unlike hair testing that can detect drug use up to 90 days. Most drugs are detectable within 1-3 days after use.³⁰ A lipid-soluble drug such as marijuana can be detected in the urine up to 1 week after use.

Factors Affecting the Accuracy of Urine Drug Tests

The accuracy of urine drug testing also depends on the volume, duration, and dosage of the drug. For example, prolonged use of benzodiazepines can be detected in the urine for up to 6 weeks, while most opioids are usually detected up to 3 days after use. Human errors and systemic errors such as contamination and mislabeling are other factors that can lead to inaccurate results.

Acute Pain

Acute pain is commonly experienced after surgery, trauma, or labor or caused by diseases such as cancer. Management of acute pain in the addicted patient often requires higher doses of analgesics than are required in the nonaddicted patient because of the phenomenon of tolerance. In patients with a history of opioid abuse, use of nonopioid therapies as well as nonpharmacological interventions can be helpful. Regional blocks, including peripheral nerve, intrathecal, or epidural blocks, are therapies to be considered in patients with drug addiction.

Opioid-addicted patients may be on methadone maintenance programs. In such cases, the baseline methadone used for drug addiction, as well as therapies for the control of postoperative pain, must be included in the perioperative pain management plan.

Use of opioids in patients with a history of addiction can lead to exacerbation of drug abuse. However, a survey of more than 10,000 patients from 151 burn centers showed no incidence of iatrogenic opioid addiction.³¹

A team-oriented, multimodal approach is necessary for the treatment of patients with drug addictions. The treatment should be consistent, structured, and developed in consultation with relevant medical specialists such as psychiatrists and addiction specialists.

Chronic Pain

Pain that continues beyond the expected time of healing or for more than 3 months is termed chronic pain. Chronic pain can develop when acute pain is prolonged and intense, such as after major surgery, after severe trauma, or as a result of painful disease states. Other factors that can play a role in chronic pain include psychiatric and medical comorbities, tobacco use, head trauma history, body mass index, sleep disorders, medications, social support levels, educational status, and current employment.

Chronic pain can result in psychological disturbances that can lead to disruption of sleep patterns, anorexia, irritability, anger, and depression. Therefore, in contrast to acute pain, the treatment of chronic pain has 2 goals: to increase patient functionality and to control pain. To achieve these goals, a number of treatment and assessment approaches have been developed.^32,33

Patients with addiction disorders should not be denied medication for pain control. Instead, their treatment plan must include awareness and treatment of the dependence.^34–36

Opioids

Opioids have long been used to treat moderate to severe chronic pain and are the cornerstone of pain control in the postoperative period. Physical dependence and tolerance occur, but the phenomenon of addiction occurs only in some patients. Depending on whether the pain state is acute or chronic, the clinician can choose a short-acting opioid such as hydrocodone, tramadol, morphine, hydromorphone, or oxycodone or a longer-acting opioid in a controlled release delivery system, such as oxycodone controlled-release, various extended-release morphine preparations, fentanyl patch, methadone, buprenorphine preparations, or levorphanol.

Discussing the patient's goals prior to the commencement of opioid therapy for chronic pain is an important step. If the goals are not met within a certain period with reasonable escalation of opioids, then alternate pain therapies and nonopioids should be considered. Weaning and cessation of opioids for a period of time and restarting opioids at a lower dose are options.³⁷ Short-acting opioids are more likely to induce abuse and tolerance than long-acting opioids such as controlled-release opioids and methadone.³⁸ Inadequate pain relief could be managed by opioid rotation and an increase in opioid doses.³⁹

Methadone can prolong the QT interval, and most clinicians require a baseline electrocardiogram prior to initiation of treatment. Further, methadone has multiple metabolism pathways, and other medicines—even over-the-counter agents—can alter its metabolism and elimination.^29,40

Oxycodone and extended-release hydromorphone have been reformulated in tamper-resistant preparations that render these agents inactive if they are crushed for snorting or injecting. In December 2012, the US Food and Drug Administration Advisory Committee on Anesthetics and Analgesics rejected the application for an extended-release hydrocodone preparation without acetaminophen (Zohydro), and 1 of the factors in the rejection was the preparation's lack of tamper-resistant safeguards.

Considerations for Patients on Methadone

Increased metabolism of methadone occurs in pregnant patients, so the dose of methadone must be adjusted accordingly. A greater incidence of spontaneous abortion occurs in pregnant patients who are using heroin (10%-20%) than in pregnant patients on methadone maintenance (3%-4%).⁴⁰ Pregnant patients on methadone maintenance should be continued on their outpatient dose in the postoperative period. Additional therapies for pain control are to be given above the maintenance dose of methadone in the postoperative period.

Considerations for Patients on Buprenorphine

The FDA approved buprenorphine in 2002 for the treatment of opioid dependence. Buprenophine is an agonist-antagonist, and pain management for patients on buprenorphine can be a challenge. The clinical efficacy of buprenorphine results from its unique molecular structure: it is a kappa agonist providing spinal cord analgesia and a partial mu opioid agonist resulting in withdrawal if patients are taking other opiate agents. Buprenorphine is used to treat addiction in the United States in the form of the sublingual preparation Suboxone, a combination of buprenorphine and naloxone. The primary role of naloxone is to prevent the abuse of Suboxone such as from intravenous injection that would result in rapid opioid antagonist effects.

Several studies in France have validated the use of buprenorphine in pregnancy for maintenance therapy.^41–43 In addition to the French studies, some American studies demonstrated positive findings for the use of buprenorphine as maintenance therapy in pregnant patients with opioid addiction.⁴² However, a Finnish study demonstrated a higher incidence of infant death and neonatal abstinence syndrome in pregnant patients on buprenorphine maintenance therapy compared to the national register.⁴³