Opioidrefractory Painful Conditions

- Pain from muscular dysfunction. In patients who present pain of myofacial nature, opioids are contraindicated since they will not result in an alleviation of nociception. Due to muscle spasm or an increase in tension physical therapy presents the first defense line in the therapeutic approach. This is accompanied by the administration of a benzodiazepine, which induces a muscle relaxant effect and/or the injection of a corticoid together with a local anesthetic (0.5% bupivacaine) in so-called trigger points (Figure II-28). Trigger points are typical points which are sore and from which the pain radiates to referred areas. Such points can be felt as knots or bumps under the palpating finger, which can be moved over the underlying musculature.

Figure 11-28. Trigger points (left) and their referred areas of radiating pain (right)

Following the in injection of the local anesthetic the circulus vituosus of increased muscle tension and myofacial pain is interrupted. Local ischemia is alleviated and local accumulation of pain mediating substances is flushed out. A typical example is tension-type headache, which is the moist common type of headache. Originating from increased stress, it is accompanied by emotional factors and fear. Thus the painful condition can be considered of psychosomatic nature.

- Pain of neurogenic or deafferentiation origin, also termed as complex regional pain syndrome (CRPS), this type of pain is mostly seen after injury of peripheral nerves leading to spontaneous and paroxysmal discharges. Such pain typically is seen as post-herpetic pain, central pain after stroke, diabetic peripheral neuropathy, phantom limb pain, traumatic nerve avulsion, trigeminal neuralgia, lumbosacral plexopathy, all being circumscribed as neuropathic pain. It originates proximal of the peripheral nociceptor (Figure II-29), and characteristically is due to a dysfunction or lesion of the peripheral nerve fibers and/or centrally located nervous structures. Typically this type of pain is accompanied by a sensory deficit: it is of a burning, shooting, stabbing, piercing, tearing or electric-shock-like, paroxysmal and vice-like nature. This pain is of paresthetic, hypo-or hyperesthetic quality often is refractory to any opioid therapy. The causes for such painful conditions may be quite different:

Figure 11-29. Compared to a normal situation (top), there is spontaneous ectopic firing from increased sodium-channel activity after peripheral nerve injury (middle), which eventually results in central sensi-tization with stimulus independent pain (bottom). Modified from [36]

o Ectopic spontaneous discharges originating from a lesioned or a cut nerve, this results in an upregulation of sodium-channels being the source of spontaneous discharge. Continuous nociceptive barrage later results in central sensi-tisation and "wind-up" (Figure II-29). o Partial denervation with spontaneous discharge of nerve activity is followed by an induced release of a nerve growth factor (NGF). Such release induces sprouting of fibers into adjacent afferent somatic nerve fibers resulting in an enlargement of the receptive field and an increased conduction of nociceptive impulses to higher pain centers (Figure II-30).

- Imbalance or loss of central inhibitory modulation within the spinal cord, due to a lesion of the descending inhibitory system, results in a decay of local inhibitory nerve cells within the spinal cord followed by an overdrive of incoming excitatory activity (Figure II-31). Such increase in the barrage of nociception is further conveyed to supraspinal pain centers resulting in sensitization.

- Sympathically maintained pain by means of a short cut of afferent, nociceptive and efferent sympathetic nerve fibers (Figure II-32). Such an emphatic sensory stimulation of sensorsy fibers by adjacent autonomic fibers is set off via sympathetic spinal ganglia, where IL-6 or the NGF induce a basketlike sprouting of sympathetic nerve fibers. By the release of noradrenalin spontaneous excitatory activity with noxious stimuli is initiated. Via the spinal ganglion pain can also be projected to corresponding areas of the skin (head zones), while through the excessive release of neurotransmitters, molecular changes, changes in gene expression within the spinal cord, and changes in the receptive fields of neurons in the perception of pain is initiated.

While opioids in such conditions often result in insufficient pain relief, therapeutically antidepressants, neuroleptics, antiarrhythmics and anticonvul-sants are the agents of choice. Also, application of a transcutaneous patch with

Figure II-30. Partial denervation results in spontaneous activity in injured afferents can produce peripheral sensitization in uninjured adjacent neurons via release of nerve growth factor (NGF). This is followed by an enlargement of painful areas with mechanical and thermal hyperalgesia. Modified from [36]

Figure II-30. Partial denervation results in spontaneous activity in injured afferents can produce peripheral sensitization in uninjured adjacent neurons via release of nerve growth factor (NGF). This is followed by an enlargement of painful areas with mechanical and thermal hyperalgesia. Modified from [36]

Figure II-31. Normally there is a balance between excitatory input from primary afferents and inhibitors input (locally and descending) at the spinal cord level. Nerve injury reduces inhibitory input with an increase in excitability in dorsal horn neurons. Primary efferents now evoke a much greater response and dorsal horn may fire spontaneously. Disinhibition of incoming nociceptive stimuli will result in subsequent "wind up". Modified from [36]

Figure II-32. Efferent mediation of pain via the spinal ganglion in sympathetically maintained nociception the local anesthetic lidocaine (being a sodium-channel blocker!) is advocated. Other topical formulations with capscaicin or EMLA cream present additional therapeutic options for treatment of neuropathic pain. In addition, transcutaneous electrical stimulation (TENS) or even spinal cord stimulation (SCS) may present an alternative and effective strategy, resulting in the attenuation of pain. In the latter technique, analgesia is induced by the electrically induced release of endogenous opioids (enkephalins, endorphins, dynorphin) in the spinal cord and within the hypothalamus activating the descending serotoninergic and noradrengergic pathways.

- Opioids in visceral painful condition. Another type of pain, which cannot be treated sufficiently with an opioid, is visceral pain. Such a painful condition may arise from the intestine (e.g. the irritable bowel syndrome or IBS) or pain emerging from other internal organs such as the gall bladder, the urinary tract or pain following an appendectomy, cholecystectomy or hysterectomy (Figure II-33). Due to the participation of smooth muscles in such a condition a peripheral analgesic with a muscle relaxant effect can be of advantage. Because the sympathetic nervous system to a major part is involved in such a condition, therapeutic implications incorporate a ganglionic blocker, surgical sympathectomy, or intravenous conduction anesthesia with guanethidine.

- Psychosomatic painful conditions, if treated with an opioid, in the long run are bound to end in opioid resistance. Such a painful condition is mainly seen in the depressive patient or it may even be a premonitoring sign of schizophrenia. However, pain can also be part of a conversion-neurotic syndrome [37, 38], where aside from pain fear, phobia, and obsessive-compulsive symptoms are the dominant elements.

Figure II-33. Pain from the viscus being transferred spinally via the anterolateral tract to the supraspinal centers

Painful conditions being sensitive to opioids All agonizing painful states, which are due to

• posttraumatic

• postoperative

• tumor origin, can be treated sufficiently with an opioid. The rational for the therapy with a central analgesic is related to the fact, that the nociceptive impulses are transmitted via specific pain afferents reaching supraspinal areas. By blockade of specific receptor sites within the brain, opioids induce a reduction and/or result in a total blockade of nociceptive impulses. Opioids therefore present the main line of defense in all medium to severe painful conditions.

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