PRINCIPLES OF MANAGING CHRONIC PAIN

   Persistent severe pain is a complex multifactorial syndrome that often becomes a more significant problem than its original cause, and effective management requires careful understanding of the neurological processes involved. Not only must the underlying pathology be addressed, but the patient must be taught to accurately report his pain, and the health care team must be taught to respond with appropriate interventions. A variety of pain measurement tools are available, from simple visual analogue scales where the patient indicates where his pain intensity lies on a linear scale, to the McGill Pain Questionnaire (MPQ) and its short form (SF-MPQ) that help ascertain not only intensity but character of experienced pain. When initial pain remedies fail, such assessment can be helpful in determining the appropriate next therapeutic step.
   The nociceptors are the primary afferent neurons whose activation is responsible for detecting painful stimuli of real or potential injury (noxious stimuli). The primary afferents, A-deltas with myelinated axons for rapid pain and unmyelinated C-fibers for dull aching pain, relay sensory information from their highly specific receptors in their receptor fields, through their dendrites, then to the axons that terminate in the dorsal root ganglia – their entry to the central nervous system. The impulses then make their way to the brain where they are interpreted and recognized as painful stimuli in order to take appropriate action. If injury is avoided, this transient pain quickly subsides without further stimulus. If injury occurs, though, more substantial acute pain tends to persist, subsiding gradually as the injury heals or as it is managed with appropriate analgesia.
   Chronic pain may be either cyclic or unrelenting and due to ongoing pathology, or it may persist beyond healing of the injury. But the differences between acute and chronic pain are more extensive that that. One difference lies in the pain threshold. A sensory neuron requires a specific level of stimulation before its action potential becomes sufficient to fire, or to generate a nervous impulse. Substance P, glutamate, aspartate, somatostatin, and cholecystokinin are all chemical nociceptive mediators produced by primary afferents and instrumental in firing the afferent neuron. Firing threshold is probably a function of numbers of such receptor sites in the synaptic gap occupied by their respective ligands. Levels of some or all of these mediators may rise with continued nociceptive stimulation, so smaller amounts released in the synaptic gaps in response to normally sub-threshold stimuli then are allowed to exceed the artificially lowered threshold to generate the pain impulse.
   On top of that, a host of inflammatory mediators (serotonin, bradykinin, histamine, potassium ions, protons, and especially prostaglandins E1, E2, and F2-alpha) produced in response to trauma, infection, or even release of the nociceptive mediators mentioned above can also lower this threshold and make the sensory afferents more sensitive to stimuli. There are also a host of nociceptors that respond not to mechanical stimuli, but to inflammation instead. The resulting hyperalgesia, abnormally low pain threshold and abnormally high intensity of perceived pain, leads to allodynia or neuropathic pain, which is perception of pain to stimuli not normally associated with pain. These actions are normally opposed by other mediators of analgesia, leu-/met-enkephalin, dynorphin, and beta-endorphin, in the dorsal horn and higher in the CNS where opioid receptors are found.
  In the chronic pain situation, inflammation and nerve damage may be generating neuropathic pain, and experience of pain can be substantially affected by anxiety, depression, cognition, emotions, and prior experience of pain. Levels of, or sensitivity to any or all of these interacting mediators may be disrupted to change the character, intensity, and sensitivity to pain. There may be no discernible cause for the pain other than persistent inflammation or the self-perpetuation of this relentless pain cycle; and disruption of that cycle has proven a tremendous challenge to the medical community.
  Broadening views of prescribing appropriately-high doses of opiates for the relief of chronic pain are increasing acceptance of such therapy, as pure opiates have essentially no ceiling dose and have been shown to cause far less end-organ damage than combination analgesics more readily available. Many types of neuropathic pain respond less well to opiate therapy and require other measures to enhance efficacy, and other aspects of quality-of-life must also be considered when treating the chronic pain patient.
  Antiepileptic drugs are largely considered the adjunctive agents of choice for neuropathic pain of a variety of types. Though the exact mechanism by which these agents diminish perceived neuropathic pain remains unknown, it probably involves membrane stabilization by slowing recovery rate of voltage-gated Na+ channels to limit repetitive firing, increase GABA levels through effects on various enzymes, binding to alpha-2-delta subunits of voltage-gated Ca++ channels, inhibiting branched-chain AA transferase, inhibiting neurotransmitter release (specifically glutamate, aspartate, GABA, acetylcholine), altering NMDA-evoked activity, and/or modulating activity at kainate and AMPA subtypes of the glutamate receptors.
   Benefits of employing benzodiazepines as adjunctive therapy in management of chronic pain is well documented. The principal modulatory site of the -aminobutyric acid (GABA) receptor complex is found on its subunit and is referred to as the benzodiazepine receptor. Three subtype receptors have been identified, and it is thought that the v1 receptor is associated with sedation and that 2 is associated with anticonvulsant, anxiolytic, and myorelaxant effects. Thus the benzodiazepines increase the inhibitory effectiveness of GABA in the spinal cord dorsal horn to suppress incoming nociceptive activity.
  Anxiolytic activity of these agents, similarly, may be useful both in treating daytime anxiety and primary nighttime insomnia (that is, insomnia not secondary to depression). Thus, these agents help to manage three distinct aspects of the chronic pain syndrome: 1.) anxiety, 2.) insomnia, and 3.) direct modulation of specific pain receptors. Discontinuation of therapy with these medications should be carefully planned and performed slowly to avoid withdrawal consequences like seizures, and resurgence of pain-exacerbating anxiety and insomnia.
  The benzodiazepines and BuSpar (buspirone) are the most widely prescribed of these agents, and may be administered during the day for daytime anxiety or at night as hypnotic agents. The particular anxiolytic can be selected for such desired pharmacologic and pharmacokinetic properties as rapidity of onset, duration of action, or accumulation/non-accumulation of active metabolites. Two non-benzodiazapine hypnotics, Ambien (zolpidem) and Sonata (zaleplon), are particularly useful to assist sleep, given their rapid onset and short-half lives, resulting in little or no grogginess upon awakening. Agents with longer half-lives (flurazepam or triazolam) may be necessary in refractory insomnia and/or opioid-tolerant patients whose induced enzyme systems have become more adept at clearing the shorter-acting agents.


Situational Depression Associated With Chronic Pain

   Patients suffering chronic pain, as with any chronic illness, are prone to clinical depression simply as a consequence of losing one’s normal life/lifestyle, of increasing dependence on others to perform what were previously simple daily functions, and of deterioration in both quality of life and life span as functions of their injuries and ensuing disabilities. Suicide is often viewed as a viable option by affected patients as a means of ending severe and unrelenting pain as well as undue financial and physical burdens created by the injury and its consequences thrust on loved ones and caregivers. Delaying or interrupting appropriate treatment of chronic pain and its consequences may not only result in needless pain and suffering, but exacerbation of existing illness necessitating more invasive and more expensive intervention, that is if not directly contributing to suicide instead.
  While the precise mechanisms involved have yet to be clearly defined, various antidepressant agents of all classes have been used successfully as adjunctive therapy to ameliorate a variety of chronic pain syndromes, including cancer pain, postherpetic neuralgia, diabetic neuropathy, fibromyalgia, headache, and low back pain, to name a few. The "opioid-sparing" utility of such antidepressant analgesics has been amply demonstrated in a number of clinical trials, with the leading hypothesis suggesting that both serotonergic and noradrenergic properties of the antidepressants are probably important and that variation among individuals in pain (as to the status of their own neurotransmitter systems) is an important variable, as are the distinct differences between chronic and acute pain regarding neurotransmitters involved and impulse transmission pathways.
   Chronic pain is a debilitating and demoralizing condition. Unable to obtain relief, patients frequently become clinically depressed and anxious, causing a vicious cycle between chronic physical pain and psychological dysfunction, where each condition exacerbates the other. Dysphoria, anhedonia, hopelessness, cognitive difficulties, loss of libido, crying spells, and suicidal ideation are depressive symptoms that frequently accompany a chronic pain syndrome.
  Comprehensive treatment of chronic pain syndrome requires that both its psychological and pharmacological management needs be addressed. The improved efficacy of the SSRIs over other antidepressant classes in treating situational depression that both results from and contributes to the chronic pain syndrome cannot be overlooked. Effective management of the depression very often improves the patient’s overall sense of well-being and enhances the benefits of other pain management measures, sometimes facilitating reductions in dosages of other medications, not to mention potentially preventing suicideTricyclic antidepressants (TCAs) are considered first-line systemic therapy for many neuropathic pain syndromes, effecting pain relief by independently providing analgesia specific for neuropathic pain, potentiating the effects of opioids, and improving underlying depression and insomnia. These agents have been established as analgesics independent of their antidepressant effects. The mechanism of action for the alleviation of neuropathic pain is thought to involve inhibition of re-uptake of serotonin and norepinephrine within the dorsal horn, but other possible mechanisms of action include alpha-adrenergic blockade, sodium channel effects (similar to local anesthetic and antiarrhythmic agents), NMDA receptor antagonism, and acting as sodium channel blockers.
   Selective serotonin reuptake inhibitors ("SSRI’s") are often useful for the pharmacological management of situational depression in patients with chronic pain syndrome. Antidepressants are especially indicated where vegetative, or biological, symptoms of depression manifest, including sleep disturbances (early morning awakening , delayed sleep onset, broken sleep, and other variants), anorexia, reduced energy level, anhedonia, and diminished libido. They are particularly appropriate as adjunctive therapy for neuropathic pain, especially when headache may be involved, with their as yet incompletely defined effects on both serotonin and norepinephrine. 
   Viagra - Chronic pain is commonly accompanied by emotional stress, increased irritability, depression, social withdrawal, financial distress, loss of libido and/or erectile dysfunction, disturbed sleep patterns, diminished appetite, and/or weight loss, which incontestably contribute to progressive deterioration of quality of life and often of existing diagnoses. Patients are frequently reluctant to disclose the existence of erectile dysfunction, preferring to suffer the disorder rather than the perceived stigma. They may be unaware that both their chronic pain and its various treatments may be directly responsible for erectile dysfunction and thus contributing to suffering.
  While the other medications in a patient’s regimen certainly can and often do cause erectile dysfunction, the innate psychogenic contribution of the chronic pain syndrome itself cannot be discounted. Probably more significant, when lower back pain is involved in spinal injuries and consequent neuropathies, especially neuropathies involving S-2,S-3, and S-4, progressive chemical radiculopathy can logically be recognized as the primary factor contributing to erectile dysfunction, making moot points of any contributing emotional factors and medication side effects. Sildenafil is an ideal choice for such neuronal dysfunction that obviously precludes normal erectile function; and the fact that it works well in a given patient lends more credence to neuropathy and radiculopathy as physical causes of dysfunction.
   While such measures as sildenafil are efforts to improve the patient’s quality of life, the value of such therapy must be recognized as having a profound impact on the patient’s affective condition, and thus the chronic pain syndrome as a whole. Just as treating the pain directly is essential, so is treatment of erectile dysfunction in order to prevent exacerbation of other symptoms. As clinicians, we are responsible for treating the whole patient, assessing and addressing the pain itself, but the side effects and impact on the patient’s entire life.