66 Analgesic Agents in Rheumatic Disease

Numerous analgesic agents can be used in the treatment of pain related to rheumatic disease.

The primary analgesic agents such as acetaminophen, nonsteroidal anti-inflammatory agents, and opioids have intrinsic analgesic properties that are most efficacious for nociceptive and inflammatory pain.

Adjuvant agents such as antidepressants, anticonvulsants, and muscle relaxants lack intrinsic analgesic properties but are effective in neuropathic and functional pain and can enhance effects of other analgesics.

The use of opioids for chronic pain remains controversial, but with proper patient selection and adherence to Universal Precautions, risks can be minimized and benefits maximized.

Many drugs can increase and decrease the metabolism of opioids through interaction of CYP2DG and CYP3A4 systems. This can greatly vary the effects of opioid in different individuals.

Increased reports of methadone overdose are thought to be due to co-administration of drugs that inhibit the CYP3A4 system.

Although the tricyclic antidepressants have been shown to be efficacious in a variety of pain syndromes, compliance is an issue because of unacceptable side effects and delayed onset.

Newer serotonin and norepinephrine reuptake inhibitors (such as duloxetine) are better tolerated and have a faster onset than older tricyclic antidepressants.

Numerous anticonvulsants have been studied with conflicting results. Only gabapentin and pregabalin consistently demonstrated efficacy in double-blind, placebo-controlled studies.1,2

Muscle relaxants are intended for short term use only and have not been shown to have long benefits.

Pain is the most common reason why patients seek medical attention, yet undertreatment of acute and chronic pain persists despite decades of efforts to provide clinicians with information about analgesics.^3,⁴ A major consequence of undertreating the patient who initially presents with pain as a result of rheumatic disease is the development of chronic pain. Chronic pain has been demonstrated to have deleterious effects on many aspects of the patient’s daily life. These effects include deterioration in physical functioning, the development of psychologic distress and psychiatric disorders, and impairments in interpersonal functioning.^5,⁶ In addition to the personal suffering it causes, chronic pain imposes a burden on society in increased health care costs, disability, and lost workdays.

Physiology of Pain Perception (the Pain Experience)

The “pain experience” involves more than just the sensation of pain. Pain activates many areas of the brain that interact, resulting in the pain experience, which will differ among individual patients. The three components of the pain experience include (1) sensory/discriminative, (2) affective/emotional, and (3) evaluative/cognitive.^7,⁸

The sensory/discriminative component of pain provides information on the intensity, location, and quality of the pain. These pathways consist of peripheral receptor activation, axon depolarization, and ascending pathways to the cortex for processing.

The ascending pathways that carry impulses from the nociceptor to the sensory cortex also give off fibers to brain stem structures and deep brain structures. Activation of these structures in the brain stem and deep brain will stimulate emotional and sympathetic responses from the individual, leading to the emotional/affective component of pain.

Finally, ascending pain pathways also send projections to the forebrain structures where the pain is processed on a cognitive and evaluative level, explaining why patients respond differently to pain based on culture, gender, and past experiences.

The main neurotransmitter in primary afferents is the excitatory amino acid glutamate. Activation of nociceptors causes the release of glutamate from presynaptic terminals in the spinal cord dorsal horn; this release acts on the ionotropic glutamate receptor amino-3-hydroxy-5-methylisoxazole-4-proprionic acid postsynaptically to cause rapid depolarization of dorsal horn neurons and, if threshold is reached, action potential discharge.^9,¹⁰

Pain Classification

Pain can be mechanistically divided into four classifications: nociceptive, inflammatory, functional, and neuropathic. Nociceptive pain is transient pain in response to a noxious stimulus that activates high threshold afferents. Nociceptive pain serves a protective function. Inflammatory pain is the spontaneous hypersensitivity to pain that occurs in response to tissue damage and inflammation (e.g., postoperative pain, trauma, arthritis). Functional pain is hypersensitivity to pain resulting from abnormal central processing of normal input (e.g., pathologic irritable bowel syndrome, fibromyalgia). Neuropathic pain is spontaneous pain and hypersensitivity to pain that occurs in association with damage to or lesions of the nervous system (e.g., peripheral neuropathy, postherpetic neuralgia). Nociceptive pain and inflammatory pain are prevalent in rheumatic disease. Functional pain and neuropathic pain are probably less prevalent in rheumatic disease; however, both should always be considered because poorly controlled pain can lead to nervous system dysfunction and functional and neuropathic pain.¹¹

Pharmacologic Treatment of Chronic Pain

The efficacy of analgesics is dependent on the pain mechanism. Primary analgesics are more efficacious in nociceptive and inflammatory pain, whereas adjuvant agents are more efficacious in neuropathic and functional pain. Each pain classification involves different pain mechanisms, and within each classification are multiple different pain mechanisms.^12,¹³

Pain is mediated through both peripheral and central mechanisms, and often more than one mechanism of pain is active in a given patient. Thus, the use of two or more agents with differing mechanisms increases the likelihood of interrupting pain signals and relieving pain.

Pharmacologic agents for the management of chronic pain are divided into primary analgesics, which have intrinsic analgesic properties, and adjunct analgesics, which may have primary analgesic properties in neuropathic pain but usually enhance the analgesic effects of primary analgesics when used in non-neuropathic pain syndromes. Table 66-1 summarizes these agents. Nonsteroidal anti-inflammatory drugs (NSAIDs)/cyclooxygenase (COX)-2 inhibitors will be discussed elsewhere (see Chapter 59).

Table 66-1 Analgesic Options to Treat Chronic Pain

Primary Analgesics	Adjunct Analgesics
Acetaminophen Nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors Opioids	Tricyclic antidepressants Serotonin-norepinephrine reuptake inhibitors Anticonvulsants Muscle relaxants Topical agents

Opioids

Numerous studies have demonstrated the efficacy of the opioids in a variety of chronic pain states, including neuropathic and non-neuropathic. However, studies to document long-term efficacy have not been conducted. Long-term opioid therapy to treat chronic pain remains controversial. Over the last century, the pendulum has swung back and forth with regard to the use of the opioids to treat pain. In the mid 20th century, opioids were limited because of fears of addiction and diversion. In the late 20th century, the pendulum went to the other side with liberal use of opioids to treat chronic pain. With the turn of the 21st century, the pendulum is moving back toward the middle with recognition of the importance of opioids in chronic pain management but an understanding of the need to balance these benefits with risks. Recently published guidelines acknowledge that opioid analgesics have an important role in pain management, and that underuse of these agents may contribute to suboptimal pain management.¹⁴ However, these guidelines also acknowledge that abuse of prescription opioids has become an epidemic, with dramatic increases seen in the United States. Therefore, a set of Universal Precautions have been developed as a guide to help the physician who prescribes opioids¹⁵ (Table 66-2).

Table 66-2 Universal Precautions for Long-term Opioid Use to Treat Pain

After conservative treatments, including nonopioids, have failed to control the patient’s pain, an opioid should be considered. In general, a short-acting weak opioid such as hydrocodone or codeine should be used first. If the patient is requiring more than three or four short-acting weak opioids per day, consider converting to a long-acting opioid. Controlled-release or long-acting opioids not only provide convenience to patients by reducing the number of daily doses required, they also provide a pharmacokinetic profile that results in reduced serum level peaks and troughs, and thereby an improvement in the consistency of effective analgesia and a potential reduction in opioid-related side effects that are often correlated with high peak serum levels. When converting to a long-acting opioid, access to a short-acting opioid for breakthrough pain can be continued, but monitored and controlled. Evaluation by a pain specialist may be considered when morphine equianalgesic dosages exceed 90 mg/day. The benefits of levels higher than 180 mg/day have not been established, and recent evidence suggests a significant increase in morbidity and mortality when doses exceed 100 mg/day.¹⁶

Opiate Receptor Classes

Early work by Martin and associates led to the postulation of three opiate receptors: mu, kappa, and sigma.^17,¹⁸ Later studies by Kosterlitz and colleagues led to the identification of the delta opioid receptor.¹⁹ With the exception of the sigma receptor, all of the opiate receptors are responsible for opioid-induced analgesia. Opioid receptors are mediated through a G protein, leading to a cascade of events that typically inhibit neuron activation.²⁰ Persistent activation of G protein–coupled receptors typically results in progressive loss of effect, known as tolerance (discussed later).

Opiate Receptor Distribution and Mechanisms of Opioid-Induced Analgesia

The main sites of action of the opiates are believed to be located in the brain and spinal cord; however, under some circumstances, peripheral mechanisms are involved. Responses of an individual patient may vary dramatically with different mu-opioid receptor (MOR) agonists. If problems are encountered with one drug, another should be tried. Mechanisms underlying variations in individual responses to morphine-like agonists are poorly understood; however, they are thought to be due to MOR polymorphisms.

Numerous sites in the brain have MORs. Activation of receptors located in the mesencephalic periaqueductal gray (PAG) appears to be the most important cause of opioid-induced analgesia. MOR agonists block release of the inhibitory transmitter γ-aminobutyric acid (GABA) from tonically active PAG systems that regulate activity in projections from the PAG to the medulla. This results in an increase in PAG outflow to the medulla, leading to activation of medullospinal projections and release of noradrenaline or serotonin at the level of the spinal dorsal horn. This release can attenuate dorsal horn excitability and analgesia. PAG activation can also increase the excitability of the dorsal raphe and the locus coeruleus, from which ascending serotonergic and noradrenergic projections originate to project to the limbic forebrain, leading to the euphoric effects sometimes experienced with systemic MOR agonists.²¹

In the spinal cord, MOR agonists are limited for the most part to the substantia gelatinosa of the superficial dorsal horn, the region in which small, high-threshold sensory afferents terminate. Most of these opiate receptors are located presynaptically and postsynaptically on small peptidergic primary afferent C fibers. Presynaptic activation of the MOR prevents the opening of voltage-sensitive Ca²⁺ channels, thereby preventing transmitter release. Postsynaptic activation of the MOR increases potassium conductance, resulting in hyperpolarization and reduced excitation induced by the presynaptic release of glutamate.²² The ability of spinal opiates to reduce the release of excitatory neurotransmitters from C fibers presynaptically and to decrease the excitability of dorsal horn neurons postsynaptically is believed to account for powerful and selective effects upon spinal nociceptive processing. In humans, an extensive literature indicates that a variety of opiates delivered spinally (intrathecally or epidurally) can induce a powerful analgesia.²²

Systemic delivery of the opioids will reduce nociceptive pain through a central mechanism located in the brain and spinal cord, as described previously, whereas the peripheral application has no effect. However, under conditions of inflammation, which result in an exaggerated pain response (hyperalgesia), the peripheral application of the opioids will reduce the hyperalgesia. This action is believed to be mediated by opiate receptors on the peripheral terminals of small primary afferents that become active under inflammatory conditions. Whether the effects are uniquely on the afferent terminal or on inflammatory cells that release products that sensitize the nerve terminal is not known.²³

Tolerance

Over time, a given dose of an opioid shows less effect and an increased dose is required to produce the same physiologic response. Tolerance to different effects of opioids occurs at different rates. For example, tolerance to sedation and nausea occurs earlier than analgesic tolerance. Some effects, such as constipation, never show tolerance.

The mechanism of opioid tolerance is controversial. Apparent opioid tolerance may be an indication of disease progression with a resultant increase in pain intensity; this is the first event that should be ruled out before true tolerance is assumed. Many cellular mechanisms can lead to tolerance. First, long-term opioid exposure can lead to receptor internalization, dephosphorylation, and desensitization. Second, exposure to high doses of opioids can lead to an increase in intracellular cyclic adenosine monophosphate (cAMP), activation of bulbospinal pathways, and glutamate receptor phosphorylation, producing an excitatory state (opioid-induced hyperalgesia).^24,²⁵ An incomplete cross-tolerance occurs between the various opioids, and when tolerance develops to one opioid, switching to another opioid can result in an increased effect.

Physical Dependence

Physical dependence is not addiction (and the terms should not be used interchangeably). Physical dependence is a pharmacologic effect characteristic of a number of different types of medications. Physical dependence is defined as the occurrence of an abstinence syndrome (withdrawal reaction) following abrupt discontinuation of the drug, substantial dose reduction, or administration of an antagonist. Physical dependence is generally assumed to occur with regular opioid use for as brief a period as a few days.

Opioid withdrawal is manifested by significant somatomotor and autonomic outflow (reflected by agitation, hyperalgesia, hyperthermia, hypertension, diarrhea, pupillary dilation, and release of virtually all pituitary and adrenomedullary hormones) and by affective symptoms (dysphoria, anxiety, and depression).²⁶ Opioid withdrawal can be minimized by slowly tapering the opioid. These phenomena are considered to be highly aversive and motivate the drug recipient to make robust efforts to avoid the withdrawal state. Initially, drug addicts are driven to repeated doses of opioids owing to the euphoric effects. However, over time, the euphoric effects are lessened, and addicts are driven to continue use to avoid withdrawal.

Addiction

Identification of the disease of addiction is important for safe and effective clinical management of pain in individuals with addictive disorders. The disease of addiction affects approximately 10% of the general population, and its prevalence may be higher in subpopulations of patients with pain. Active addiction is a contraindication to the use of the opioids; a past history is a relative contraindication, but opioids can be used successfully with appropriate monitoring. A persistent misunderstanding is prevalent among health care providers, regulators, and the general population regarding the nature and manifestations of addiction, which may result in undertreatment of pain and stigmatization of patients using opioids for pain control.

Evaluating for addiction in a patient who is prescribed long-term opioids for pain control is often problematic. This risk of opioid addiction and misuse can be assessed with validated questionnaires (Table 66-3).²⁷ Although the concept of addiction may include the symptoms of physical dependence and tolerance, physical dependence or tolerance alone does not equate with addiction. In the chronic pain patient taking long-term opioids, physical dependence and tolerance should be expected, but the maladaptive behavior changes associated with addiction are not expected.^28,²⁹

Table 66-3 Opioid Risk Tool

	Male	Female
Family History (Parents and Siblings)
Alcohol abuse	_____(3*)	_____(1)
Illegal drug use	_____(3)	_____(2)
Prescription drug abuse	_____(4)	_____(4)
Personal History
Alcohol abuse	_____(3)	_____ (3)
Illegal drug use	_____(4)	_____ (4)
Prescription drug abuse	_____(5)	_____ (5)
Mental Health
Diagnosis of ADD, OCD, bipolar, schizophrenia	_____ (2)	_____ (2)
Diagnosis of depression	_____ (1)	_____ (1)
Other
Age 16-45 years	_____ (1)	_____ (1)
History of preadolescent sexual abuse	_____ (0)	_____ (3)
Total	_____	_____

ADD, attention deficit disorder; OCD, obsessive-compulsive disorder.

^* Numbers in parentheses indicate points. Scoring:

0-3: low risk: 6% chance of developing problematic behaviors.

4-7: moderate risk: 28% chance of developing problematic behaviors.

≥8: high risk: >90% chance of developing problematic behaviors.

Adapted from Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool, Pain Med 6:432–442, 2005.

Addiction is a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use in spite of potential harm. For patients with continuous pain, inadequate pain management (e.g., PRN dosing schedule, use of drugs with inadequate potency, use of dosing intervals that are too long) can lead to behavioral symptoms that mimic those seen with psychological dependence and can be mistaken for addiction termed pseudoaddiction. In the case of pseudoaddiction, problem behaviors resolve after sufficient pain relief is established. However, behaviors related to true addiction may also resolve after dose escalation. Thus, it can be difficult to distinguish pseudoaddiction from true addiction; careful evaluation and management may be required until the circumstances are sorted out ³⁰ (see Table 66-3).

Opioid Pharmacology

Morphine

Morphine is the gold standard against which all other opioids are measured. Morphine can be administered by oral, rectal, subcutaneous, intravenous, intramuscular, and intraspinal routes. Oral bioavailability of morphine is about 25% (range, 10% to 40%). Peak plasma concentrations occur 0.5 to 1 hour after ingestion with a half-life of around 3 to 4 hours. To increase the dosing interval of oral morphine, several sustained- and controlled-release preparations have been developed (Table 66-4). The average protein binding of morphine is around 35%, but this decreases with renal and hepatic dysfunction. Because of the hydrophilicity of morphine, there is poor central nervous system (CNS) penetration and little tissue accumulation with repeated dosing. Morphine is metabolized primarily in the liver to two main metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M3G is the primary metabolite with potent CNS excitatory properties. Because of its polarity, CNS penetration is poor; however, in renal failure, M3G plasma concentrations can be high enough to drive this metabolite into the CNS, leading to excitation. M6G possesses potent MOR agonism, but because of its high polarity, CNS penetration is poor. However, like M3G, M6G can accumulate in renal impairment, leading to exaggerated opioid effects. Only about 10% of unmetabolized morphine is excreted renally, whereas 90% is excreted renally as morphine glucuronide (70% to 80%) and normorphine (5% to 10%) conjugates.³¹

Table 66-4 Opioid Drug Interactions

Toxicity

Respiration

Although effects on respiration are readily demonstrated, clinically significant respiratory depression rarely occurs with standard analgesic doses in the absence of other contributing comorbidities or concomitant use of sedatives. In addition, the respiratory depressant effect of the opioid is significantly reduced with continued opioid use owing to tolerance. It should be stressed, however, that respiratory depression represents the primary cause of morbidity secondary to opiate therapy.⁴⁷ In humans, death from opiate poisoning is nearly always due to respiratory arrest or obstruction.⁴⁸ For example, In November of 2006, the FDA notified health care professionals of reports of death and life-threatening adverse events, such as respiratory depression and cardiac arrhythmias, in patients receiving methadone (FDA ALERT [11/2006]: Death, narcotic overdose, and serious cardiac arrhythmias, www.fda.gov/cder/drug/infopage/methadone). Methadone appears to be involved in approximately one-third of all prescription opioid–related deaths, exceeding hydrocodone and oxycodone despite being prescribed one-tenth as often. This has led to revisions in methadone conversion tables.

At therapeutic doses, opiates depress all phases of respiration (rate, minute volume, and tidal exchange). High doses can produce irregular and agonal breathing.⁴⁸ A number of factors can increase the risk of opioid-induced respiratory depression, even at therapeutic doses. These include (1) concomitant use of sedatives such as alcohol, benzodiazepines, and tranquilizers, (2) obstructive and central sleep apnea, (3) extremes in age (both newborns and elderly), (4) comorbidities such as pulmonary disease and renal disease, and (5) removal of the painful stimulus. Pain serves as a respiratory stimulant, and removal of pain (e.g., neurolytic block with severe cancer pain) will reduce the ventilatory drive, leading to respiratory depression.