CHAPTER 157 Pharmacologic Treatment of Pain
The Phenomenon of Pain
Pain is the unpleasant physical and emotional experience associated with tissue damage—either impending or actual—and involves sensations transmitted from the periphery to the central nervous system for processing and perception. The physical phenomenon of pain signal transduction and transmission is complemented by the neuropsychological process of perceiving pain signals and their meanings. A close relationship between pain perception and culture has been identified,1 and studies demonstrate that experiences of pain intensity vary with differences in the attitudes, beliefs, and emotional and psychological state of the patient.2 Pain perception and response integrate the physiologic, cognitive, and behavioral resources necessary to promote survival when body integrity is compromised. Patients experiencing pain report higher levels of physical and emotional distress; they behave differently from persons without pain, in a way that is distinguished not just by how they feel but also by their behavior. To effectively treat pain, an appreciation of the neurophysiology and psychology of pain perception is essential.
Acute pain is nociceptive pain that is generated in reaction to focal peripheral nerve or tissue injuries such as traumatic or operative tissue damage. Acute pain usually resolves as tissues heal and inflammation subsides. Chronic pain persists beyond the usual course of injury and healing and includes persistent pain that does not respond to routine pain control measures.3 Chronic pain has many causes, but primary groups include general/mixed pain, neuropathic pain, osteoarthritis, and back and leg pain. It is estimated that between 2 and 6 million Americans cope with neuropathic pain.4 A World Health Organization study in 1997 found that 22% of primary care patients reported pain lasting more than 6 months.5 It is estimated that half of elderly people live with chronic pain.6
Pain patients consume more health care resources, including increased visits for lower priority medical problems. The exact explanation for this correlation is unclear, but it is probably due to a combination of comorbid chronic disease, psychogenic comorbidity, and chronic pain comorbidity.7 Patients with chronic back pain accrue annual health care expenses of $91 billion for treatment of all conditions.
Pain Perception and Relay
Although segmenting pain neurobiology into peripheral and central mechanisms can facilitate an understanding of the pathophysiology and treatment of pain, the pathways are interrelated, and multiple neuropeptides and neurotransmitters are involved along the signaling pathways after a painful stimulus. Conversion of a mechanical, chemical, or thermal stimulus to an electrical signal, termed transduction, is performed by nociceptive neurons. Small myelinated Aδ fibers rapidly transmit signals to the central nervous system, whereas unmyelinated C-fibers transmit signals more slowly. Transduction is facilitated by voltage-gated sodium channels, of which there are numerous subtypes. Recent research has shown that the Nav1.7 channel is involved in pain transduction abnormalities in several disorders. A gain-of-function mutation in the Nav1.7 channel is responsible for intractable pain in primary erythromelalgia and paroxysmal extreme pain disorder. A loss-of-function mutation appears key to the disorder congenital indifference to pain.8
Tissue damage releases factors, including histamine, serotonin, bradykinin, substance P, and prostaglandins, that catalyze the local inflammatory response by sensitizing already-activated nociceptors and activating dormant ones. Prostaglandin E2 (PGE2) has been demonstrated to activate ion channels in peripheral neurons. PGE2 also sensitizes dorsal horn neurons to thermal and mechanical stimuli.9 Substance P stimulates release of factors from mast cells that result in vasodilation and increased vascular permeability.
Loss of synaptic inhibition induced by inflammation or nerve injury, or both, can lead to hyperactivity of nociceptors, which is termed peripheral sensitization. Hyperexcitability of peripheral sensory neurons develops as a result of inflammation, reparatory mechanisms, and adjacent tissue reactions. It results in the metabolic activation and hyperexcitation of spinal nociceptive neurons, expansion of sensory receptive fields, and alterations in the processing of generally innocuous stimuli. Release of leukotrienes, cytokines, and neurotropic factors at the site of injury results in upregulation of sodium channels in nociceptor cells, conformational changes in transducer proteins, and increased calcium influx into second-messenger systems. The end result of this excitation is increased ectopic activity in peripheral neurons because increased voltage-gated ion channel activity leads to more subthreshold membrane potentials and a higher likelihood of ectopic action potential firing.10 The increased peripheral excitation can lead to central sensitization as the higher order neurons receive a barrage of signals from hyperactive peripheral neurons. The increased signaling is the result of temporal summation of C-fiber signals. A higher frequency of firing creates sustained excitatory postsynaptic potentials in the dorsal horn, each lasting up to 20 seconds and leading to the release of excitatory amino acids such as glutamate. Temporal summation in the central pain-projecting neurons leads to a hyperactivated state in which subsequent C-fiber input further increases the action potential strength.11
Transmission of the nociceptive signal proceeds from the second-order neurons within the substantia gelatinosa through the spinothalamic tract into the thalamus. The periaqueductal gray matter within the midbrain is a major nociceptive integration site where there are high concentrations of opioid receptors and neuroactive peptides. Other sites of involvement in pain transduction include the somatic sensory cortex, periaqueductal gray matter, periventricular gray matter, ventral medulla, nucleus raphe magnus, and limbic system. Functional magnetic resonance imaging (fMRI) studies of nociceptive stimulation show activation in the thalamus, secondary somatosensory cortex, ipsilateral insular cortex, and anterior cingulate cortex.12 fMRI studies looking at the response to opioids identify the interplay of the dorsolateral prefrontal cortex, temporal lobe, inferior parietal lobe, anterior cingulate cortex, nucleus accumbens, orbital gyrus, substantia nigra and putamen, and hippocampus (Fig. 157-1).13
Signals transmitted to the cerebral cortex variably emerge into conscious perception. Coordinated actions among subcortical and cortical areas create the subjective, affective, and cognitive responses that determine an individual’s reaction to the pain. The insula is the most frequently activated structure in fMRI pain studies and serves as a center for the integration of neural impulses.14 Damage to the insula can lead to pain asymbolia.15 The significance of pain is conveyed through connections between the insula and the striatum to parietal association cortices and the lateral prefrontal cortices.16 Supratentorial influences can dampen the pain, as in the case of an injured person who continues activities because the circumstances require self-preservation. In these cases, central neurons downregulate the perception of pain at the level of the spinal cord and dorsal horn by releasing endogenous opioid neuropeptides (endorphins, enkephalins, dynorphins), norepinephrine, GABA, and serotonin.
Treatment of Pain
Pharmacologic Agents
Nineteenth century physicians relied on an armamentarium of medications for pain control that included opium, morphine, codeine, and cocaine. The development of aspirin in 1897, the first compounded analgesic, revolutionized the treatment of pain. In the following century, numerous other agents were developed, with varying efficacy for a spectrum of pain conditions. Agents that are considered first line in the treatment of acute pain include opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), but these agents are less effective for neuropathic pain. Recommended first-line treatment of chronic neuropathic pain includes tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, calcium channel α2δ ligands, and topical lidocaine. Second- and third-line therapies such as opioid analgesics, anticonvulsants, and antidepressants are more variable in their effectiveness and have broader side effect profiles, which limits their use (Table 157-1 and Fig. 157-2).
| PAIN SOURCE | POTENTIAL AGENTS |
|---|---|
| Trauma/surgery/procedures | NSAIDs, opioids, acetaminophen, epidural analgesia |
| Acute sickle cell or cancer pain exacerbations | Opioids, NSAIDs, acetaminophen, steroids |
| Chronic low back pain | NSAIDs, opioids, muscle relaxants |
| Diabetic peripheral neuropathy | Antidepressants, anticonvulsants, capsaicin |
| Trigeminal neuralgia | Carbamazepine, baclofen, phenytoin |
| Postherpetic neuralgia | Antidepressants |
| Phantom limb pain | Carbamazepine, mexiletine, epidural analgesia |
| Cancer/HIV disease | Multiple combinations |
HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs.
Acetaminophen
Although acetaminophen is often grouped with the NSAIDs because of its mild side effect profile and its effectiveness in analgesia and antipyresis, it does not produce an anti-inflammatory effect. The medication’s mechanism of action is still poorly understood but is believed to be related to a decrease in prostaglandin production through reduction of the oxidized form of COX and selective inhibition of prostaglandin H2 synthase.17–19 Additional research suggests that an acetaminophen metabolite may block the uptake of anandamide and consequently inhibit vanilloid receptor activation in nociceptors. There also appears to be a central effect on COX-3 inhibition leading to decreased PGE2 concentrations within the brain.20 Adverse effects include hepatotoxicity, most often associated with intentional overdose and patients with a history of alcohol abuse. Acetaminophen is only a weak inhibitor of platelet COX-1, and therefore the platelet inhibition effect is more limited than that with NSAIDs.
Opioids
Opioids are one of the most effective classes of medications available to treat both acute and chronic pain and are therefore a mainstay for both types of pain. In one study examining the treatment of chronic central pain, patients’ pain intensity scores were significantly lower after the administration of opioids than after placebo.21 Opioids act to suppress pain through mu-receptor activation on primary afferent nerve fibers, dorsal horn neurons, and supraspinal pain center neurons. Presynaptic activation by bound opioids reduces neurotransmitter release, whereas postsynaptic activation causes hyperpolarization through increased conductance of potassium.22 Opioids were originally thought to be ineffective for neuropathic pain,23 but more recent trials have demonstrated that pain intensity scores were significantly lower after opioid administration than after placebo for neuropathic pain.24
The most common reasons that patients discontinue opioid therapy are inadequate analgesia and intolerable side effects.25 In one prospective study, 17% of patients withdrew because of adverse events and 8% because of lack of efficacy (Table 157-2).26 In general, side effects can be addressed by decreasing the dose or changing the route of administration. Opioid rotation, in which the opioid is combined with other medications in a complementary strategy, or using a second medication targeting the side effect can also alleviate side effects.27 The most commonly prescribed opioid medications are morphine, codeine, oxycodone, hydrocodone, fentanyl, alfentanil, meperidine, propoxyphene, and methadone. Each varies in side effect profile, drug-drug interactions, and therapeutic effects. All members of the opioid class cross the placenta, although no teratogenic effects have been observed. If used during labor, the medications can cause neonatal depression. Interestingly, in Japan, opioids are rarely prescribed because other medications appear to provide satisfactory levels of relief.28
| SIDE EFFECT | MECHANISM |
|---|---|
| Neurological | Delirium, hallucination, euphoria, sedation/drowsiness, dizziness, diminished psychomotor performance, seizures, headaches, muscle rigidity, hyperalgesia, paradoxical pain |
| Cardiopulmonary | Cardiac dysrhythmias (bradycardia/long QTc, torsades de pointes), hypotension, decreased systemic vascular resistance, noncardiogenic pulmonary edema, respiratory depression |
| Gastrointestinal | Nausea and vomiting, constipation, gastroesophageal reflux disease, xerostomia, biliary duct obstruction |
| Genitourinary | Altered kidney function, urinary retention, peripheral edema |
| Endocrinologic | Hypogonadism, sexual dysfunction, osteoporosis |
Tramadol is an atypical opioid related to codeine. It exerts some of the pain-relieving properties of opioids while having a more tolerable side effect profile by acting as a norepinephrine and serotonin reuptake inhibitor. Its primary metabolite, O-desmethyltramadol, has mu-opioid agonist activity, which provides tramadol a potency about 10% of morphine. Tramadol has been shown to cut pain levels by more than 50% in the treatment of neuropathic pain.29 Adverse effects include nausea, sweating, vomiting, dry mouth, constipation, dizziness, sedation, and incoordination. There are also smaller risks of a reduced seizure threshold, respiratory depression, withdrawal symptoms, and serotonin syndrome. Caution should be exercised in prescribing tramadol to elderly patients because it can cause cognitive impairment. It has been demonstrated to have a much lower risk for abuse than other opioid drugs,30 and it does not have the gastrointestinal side effects associated with NSAIDs (Table 157-3).
