Combination Spinal Analgesic Chemotherapy: A Systematic Review

In the 25 years since the first application of spinal opioids for treating cancer pain, this mode of analgesia has grown to enjoy worldwide use (1,2). A natural outgrowth of local-anesthetic spinal anesthesia, “the major advantages of ‘selective’ blockade of pain by spinal opioids [lay] in the absence of sympathetic blockade and postural hypotension, potentially allowing easy ambulation of patients, and avoidance of cardiovascular collapse or convulsions—the major complications of local anesthetic blockade”(3). Perioperative epidural analgesia is increasingly recognized to influence surgical outcomes and the likelihood of developing chronic pain states, and technical refinements in delivery systems (4) allow chronic spinal drug delivery for management of previously refractory cancer pain (5–7). Such progress reflects the rapid maturation of the practice of spinal analgesia since the previous frequently cited (8) review of this topic (3). During these same two decades, advances in preclinical pain research have led to recognition of the spinal cord as a key target for inhibition of acute nociception and preemption of “pain memory”(9). It is now clear that the customary distinction between acute and chronic pain is an oversimplification because key psychological and physiological responses traditionally associated with persistent pain (gene expression and neuronal sensitization and remodeling) rapidly follow acute injury (10). Persuasive evidence has emerged that persistent pain, regardless of its cause, constitutes a pathologic state per se in which spinal neuronal reorganization (“plasticity”) exaggerates and perpetuates nociception and pain (11–13). Insight into spinal cord pathophysiology and pharmacology has spurred novel drug discovery and rekindled interest in spinal delivery of established drugs (14,15). In an effort to gain better control over pain acutely and to maintain such control over the long term (16,17), anesthesiologists and others involved in the treatment of pain have advanced from single-drug spinal drug therapy to the coadministration of two and three drugs. Unfortunately, the standards of rigorous clinical evidence have almost wholly been ignored during this progress, and uncontrolled case series or case reports form by far the largest proportion of this literature (18). Considering that the number of possible combinations of different analgesics increases as a factorial function of the number of available choices, the optimum choices and relative doses of drugs to apply to different patient populations with different origins of pain require extensive clinical study (19). At the same time, knowledge of the neurotransmitters, membrane receptors, and intracellular mediators involved in dorsal horn nociceptive processing has evolved to reveal a remarkable diversity (Fig. 1). The growing trend of using spinal drug combinations that target multiple mechanisms of analgesia mirrors multidrug therapy in many medical disciplines and has been termed combination analgesic chemotherapy(11).Figure 1: Possible arrangement of pre- and postsynaptic receptors on structures in the dorsal horn of the spinal cord, and potential sites of action of opioid and non-opioid spinal analgesics. Presynaptic release of the neurotransmitter glutamate (Glu) results in activation of the postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which controls a rapid-response sodium (Na+) channel. Substance P (SP) interacts with the neurokinin (NK-1) receptor and results in activation of second messengers. With prolonged activation, the N-methyl-d-aspartate (NMDA) receptor is primed, Glu activates the receptor, the magnesium (Mg2+) plug is removed, and the ion channel allows entry of Na+ and calcium (Ca2+) ions. The increase in intracellular Ca2+ then triggers a number of second-messenger cascades. Production of nitric oxide (NO) increases via the Ca2+/calmodulin-dependent enzyme NO synthase. NO may diffuse out of the neuron to have a retrograde action on primary afferents and also activates guanylyl cyclase, leading to increases in intracellular cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinases. Activation of the Ca2+-dependent protein kinase C γ isoform (PKCγ) leads to phosphorylation of the NMDA receptor, which reduces the Mg2+ block (dotted line II) relating to the development of opioid tolerance. The increase in intracellular Ca2+ also results in the induction of protooncogenes such as c-fos, with a presumed action on target genes of altering long-term responses of the cell to further stimuli. κ, μ, and δ = opioid receptors; GABA = γ-aminobutyric acid; α2 = α2 adrenoceptor; 5-HT = serotonin. Details of the potential analgesics are outlined in the text. NSAID = nonsteroidal antiinflammatory drug; SNX-111 and AM336 = omega conopeptides that block neuronal Ca2+ channels. DAMGO = [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin; R-Pia = R-phenyl-isopropyl-adenosine; Neca = N-ethylcarboxamide-adenosine.This review systematically examines one emerging aspect of spinal opioid and non-opioid analgesia; namely, the application of drug combinations for spinal analgesia. We omit for space considerations other topics that have recently been reviewed (e.g., outcomes of spinal regional analgesia) (20,21), are beyond the scope of this brief survey (e.g., relative merits of spinal and systemic analgesia), or that are now so established as to be primarily of archival or reference interest (e.g., physicochemical properties of opioids) (11). 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