Question

Using specific examples, discuss how drug extension of morphine is achieved (mechanistically) and impacts on pharmaceutical (analgesic) activity.

Answer 1

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CONTROL of severe pain with administration of intrathecal medication is an important area in which much investigation has been done yet much remains be done.1 Whereas most studies have focused on postsurgical or neuropathic pain, visceral pain pathways and development of treatments for visceral pain in animal models that closely resemble human conditions remain relatively less well unexplored.2 Pain is the primary manifestation and cause of suffering in patients with inflammatory conditions or cancer of visceral organs. Clinical management of acute and chronic visceral pain presents a number of challenges. For example, adequate doses of opioid drugs are often accompanied by significant undesirable side effects such as tolerance, constipation, sedation, and other mental status changes, and eventual habituation and dependence with long-term administration in many patients.3 In addition to oral, transcutaneous, and intrathecal pharmacologic therapy to manage intractable pain, neurolytic blocks of the sympathetic axis are often recommended for temporary pain relief in patients with visceral pain.4,5 Surgical disruption of nociceptive system components is the last line of therapy used as opioid medications become limited by tolerance and side-effects.6 A midline dorsal column lesion has been shown to be an effective surgical treatment for the relief of pelvic or thoracic visceral pain in patients, although this approach has been limited to terminal cancer patients.7,8 The paucity of basic pharmacological information about visceral pain hinders efforts to develop better treatment strategies for clinical use.9,10

Morphine sulfate, a mu-opioid receptor agonist, and lidocaine, a sodium channel antagonist, have for decades been the primary pharmacological agents used for pain control via spinal administration. Morphine is the most widely used drug for chronic intrathecal infusion. Because of its undesirable side effects at therapeutic concentrations, numerous studies have been undertaken to find other medications that potentiate the effects of morphine so that a lower dose can be used to achieve satisfactory pain control or medications that can replace morphine altogether. Among the medications explored are N -methyl-d-aspartate receptor antagonists,11 γ-aminobutyric acid (GABA) analogs and GABA-receptor agonists,12,13 ion channel (Na+, K+, Ca++, and Cl-) modulators,14 and other classes of medications such as tricyclic antidepressants and antiepileptic drugs. The results of studies with some of these medications alone and in combination with morphine have been promising.1 Use of intraperitoneal injection of a local anesthetic (such as ropivacaine) significantly decreases postoperative visceral pain15–17 and has been used in combination with morphine. However, respiratory depression has been reported when the effects of bupivicaine wear off when combined with morphine.