PAIN AND ANALGESIC PHARMACOLOGY

Pain is an unpleasant sensory and emotional experience that serves to alert an individual to actual or potential tissue damage. This damage can be caused by exposure to noxious chemical, mechanical, or thermal stimuli (e.g., acids, pressure, percussion, and extreme heat) or by the presence of a pathologic process (e.g., a tumor, muscle spasm, inflammation, nerve damage, organ distention, or other mechanism that activates nociceptors on sensory neurons). Although pain serves a protective function by alerting a person to the presence of a health problem, its non- restrained expression often leads to considerable morbidity and suffering. For this reason, analgesics or drugs that relieve pain are used for symptomatic treatment of pain from a wide variety of disease states, ranging from acute and chronic physical injuries to terminal cancer.

Based on their mechanisms of action, analgesics can be classified as opioid analgesics or nonopioid analgesics. Opioid analgesics act primarily in the spinal cord and brain to inhibit the neurotransmission of pain. In contrast, nonopioid analgesics act primarily in peripheral tissues to inhibit the formation of algogenic or pain-producing substances such as prostaglandins. Because most of the nonopioid analgesics also exhibit significant antiinflammatory activity, they are called nonsteroidal antiinflammatory drugs (NSAIDs).

To facilitate the selection of an appropriate analgesic or anesthetic medication, patients are usually asked to describe their pain in terms of its intensity, duration, and location. In some cases patients report an intense, sharp, or stinging pain. In other cases they describe a dull, burning, or aching pain. These two types of pain are transmitted by different types of neurons and their primary afferent fibers. Pain can be further distinguished on the basis of whether it is somatic, visceral, or neuropathic in origin. Somatic pain is often well localized to specific dermal, subcutaneous, or musculoskeletal tissue. Visceral pain originating in thoracic or abdominal structures is often poorly localized and may be referred to somatic structures. For example, cardiac pain is often referred to the chin, neck, shoulder, or arm. Neuropathic pain is usually caused by nerve damage, such as that resulting from nerve compression or inflammation, or from diabetes. Neuropathic pain is characteristic, for example, of trigeminal neuralgia (tic douloureux), postherpetic neuralgia, and fibromyalgia.

PAIN PATHWAYS Exposure to a noxious stimulus activates nociceptors on the peripheral free nerve endings of primary afferent neurons. The cell bodies of these neurons sit alongside the spinal cord in the dorsal root ganglia and send one axon to the periphery and one to the dorsal horn of the spinal cord. With noxious stimulation, substance P, glutamate, and other excitatory neurotransmitters are released from the central terminations of the primary afferent fibers onto neurons of the spinal cord. Many of these terminals synapse directly on spinothalamic tract neurons in the dorsal horn, which send long fibers up the contralateral side of the spinal cord to transmit pain impulses via ascending pain pathways to the medulla, midbrain, thalamus, limbic structures, and cortex.

The primary afferent fibers transmitting nociceptive information are Aδ fibers and C fibers, which are responsible for sharp pain and dull pain, respectively. Spinal reflexes activated by these fibers can lead to withdrawal from a noxious stimulus before pain is perceived by higher structures. Ascending pain pathways consist of two main anatomic-functional projections: the sensory discriminative component, to the cerebral cortex, and the motivational-affective component, to the limbic cortex. Projections to the sensory cortex alert an individual to the presence and anatomic location of pain, whereas projections to limbic structures (e.g., the amygdala) enable the individual to experience discomfort, suffering, and other emotional reactions to pain.

The activation of spinothalamic neurons in the spinal cord is modulated by descending inhibitory pathways from the midbrain and by sensory Aβ fibers arising in peripheral tissues. These two systems constitute the neurologic basis of the gate-control hypothesis. According to this hypothesis, pain transmission by spinothalamic neurons can be modulated, or gated, by the inhibitory activity of other types of large fibers impinging on them. The activation of spinothalamic neurons is inhibited by peripheral Aβ sensory fibers that stimulate the release of met-enkephalin from spinal cord interneurons. The Aβ fibers are thought to also mediate the analgesic effect produced by several types of tissue stimulation, including acupuncture and transcutaneous electrical nerve stimulation(TENS). These mechanisms explain the pain relief that may be produced by simply rubbing or massaging a mildly injured tissue.

The descending inhibitory pathways arise from periaqueductal gray (PAG) in the midbrain, and they project to medullary nuclei that transmit impulses to the spinal cord. The medullary neurons include serotonergic nerves arising in the nucleus magnus raphe (NMR) and noradrenergic nerves arising in the locus ceruleus (LC). When these nerves release serotonin and norepinephrine in the spinal cord, they inhibit dorsal spinal neurons that transmit pain impulses to supraspinal sites. Nerve fibers from the PAG also activate spinal interneurons that release an endogenous opioid peptide, met-enkephalin. The enkephalins act presynaptically to decrease the release of pain transmitters from the central terminations of primary afferent neurons. They also act on postsynaptic receptors on spinothalamic tract neurons in the spinal cord to decrease the rostral transmission of the pain signal. Opioid analgesics activate the descending PAG, NMR, and LC neuronal pathways, and they also directly activate opioid receptors in the spinal cord.

Opioid Agonists Opiates are drugs obtained from opium, a derivative of the poppy plant. Opiates have been used to treat pain for over 200 years. Opioid agonists mediate their effects at three types of opioid receptors: μ (mu) opioid receptors, δ (delta) and kappa (κ). There are three major families of endogenous opioid peptides: enkephalins, β-endorphins, and dynorphins.

Mechanism of Action The opioid receptors are prominent members of the G protein–coupled receptor superfamily. Activation of opioid receptors leads to inhibition of adenylyl cyclase and a decrease in the concentration of cyclic adenosine monophosphate an increase in K+ conductance, and a decrease in Ca2+ conductance . These actions cause both presynaptic inhibition of neurotransmitter release such as glutamate and substance P from the central terminations of small-diameter primary afferent fibers and postsynaptic inhibition of membrane depolarization of dorsal horn nociceptive neurons.

NSAIDs

TREATMENT OF NEUROPATHIC PAIN Neuropathic pain is the severe, debilitating, chronic pain that occurs in conditions such as trigeminal neuralgia, diabetic neuropathy, postherpetic neuralgia and phantom limb pain, affecting millions of people worldwide. It is often stated that neuropathic pain is opioid- resistant. However, clinical studies have shown opioids such as morphine, oxycodone, levorphanol, tramadol and tapentadol to be effective in the treatment of neuropathic pain, provided an adequate dose can be reached that provides analgesia without excessive side effects. The monamine uptake inhibiting properties of tramadol and tapentadol may contribute to their effectiveness.

Tricyclic antidepressants, particularly amitriptyline, nortriptyline and desipramine are widely used. These drugs act centrally by inhibiting noradrenaline reuptake and are highly effective in relieving neuropathic pain in some, but not all, cases. Their action is independent of their antidepressant effects. Drugs such as duloxetine and venlafaxine, which inhibit serotonin and noradrenaline uptake, are also effective and have a different side effect profile, but selective serotonin reuptake inhibitors show little or no benefit. Gabapentin and its congener, pregabalin, are antiepileptic drugs that are also effective in the treatment of neuropathic pain. They reduce the expression of α2δ subunits of voltage-activated calcium channels on the nerve membrane and reduce neurotransmitter release. The α2δ subunits are upregulated in damaged sensory neurons, thus explaining why these agents are more effective across a range of pain states associated with nerve damage than in other forms of pain.

Carbamazepine, another type of antiepileptic drug, is effective in trigeminal neuralgia but evidence for effectiveness against other neuropathic pains is lacking. Carbamazepine blocks voltage-gated sodium channels being slightly more potent in blocking Nav1.8 than Nav1.7 and Nav1.3 channels; all of these channel subtypes are thought to be upregulated by nerve damage and contribute to the sensation of pain. At higher concentrations, it inhibits voltage-activated calcium channels. Other antiepileptic agents such as valproic acid, lamotrogine, oxcarbazepine and topiramate, may have efficacy in some neuropathic pain states. Lidocaine (lignocaine), a local anaesthetic drug, can be used topically to relieve neuropathic pain. It probably acts by blocking spontaneous discharges from damaged sensory nerve terminals.

TREATMENT OF FIBROMYALGIA Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue and insomnia. Its cause is unknown, with no obvious characteristic pathology being apparent. It is associated with allodynia. As with neuropathic pain, classical analgesics (i.e NSAIDs and opioids), while bringing some relief, are not very effective in treating this disorder. Various antidepressant drugs (e.g. amitriptyline, citalopram, milnacipram, duloxetine, venlafaxine), antiepileptic agents (e.g. gabapentin, pregabalin), benzodiazepines (e.g. clonazepam, zopiclone) are currently used for this disorder – this long list reflecting their uncertain efficacy.