The Genesis of Pain Medicine as a Subspecialty in Anesthesiology.

Certification in pain medicine as a subspecialty in Anesthesiology was conceived in 1989 and first discussed by the American Board of Anesthesiology in 1990. Shortly thereafter, the ABA submitted an application to the American Board of Medical Specialties for recognition to certify in pain management. That was approved in 1991. The Accreditation Council of Graduate Medical Education approved an application from the Anesthesiology Residency Review Committee to accredit programs in pain management education and training in 1992. The first examination for Pain Management certification was given in 1993. The certificate was modified in 2002 to Pain Medicine rather than Pain Management. Five member boards of ABMS are now approved for certification in pain medicine and all use the ABA Pain Medicine examination.

Pain tests provoke modality-specific cardiovascular responses in awake, unrestrained rats.

Nociception modulates heart rate (HR) and mean arterial pressure (MAP), suggesting their use of HR and MAP as indicators of pain in animals. We explored this with telemetric recording in unrestrained control and neuropathic (spinal nerve ligation) rats. Plantar stimulation was performed emulating techniques commonly used to measure pain, specifically brush stroke, von Frey fiber application, noxious pin stimulation, acetone for cooling, and radiant heating, while recording MAP, HR, and specific evoked somatomotor behaviors (none; simple withdrawal; or sustained lifting, shaking, and grooming representing hyperalgesia). Pin produced elevations in both HR and MAP, and greater responses accompanied hyperalgesia behavior compared to simple withdrawal. Von Frey stimulation depressed MAP, and increased HR only when stimulation produced hyperalgesia behavior, suggesting that minimal nociception occurs without this behavior. Brush increased MAP even when no movement was evoked. Cold elevated both HR and MAP whether or not there was withdrawal, but MAP increased more when withdrawal was triggered. Heating, consistently depressed HR and MAP, independent of behavior. Other than a greater HR response to pin in animals made hyperalgesic by injury, cardiovascular events evoked by stimulation did not differ between control and neuropathic animals. We conclude that (a) thermoregulation rather than pain may dominate responses to heat and cooling stimuli; (b) brush and cooling stimuli may be perceived and produce cardiovascular activation without nocifensive withdrawal; (c) sensations that produce hyperalgesia behavior are accompanied by greater cardiovascular activation than those producing simple withdrawal; and (d) von Frey stimulation lacks cardiovascular evidence of nociception except when hyperalgesia behavior is evoked.

Depletion of calcium stores in injured sensory neurons: anatomic and functional correlates.

BACKGROUND: Painful nerve injury leads to disrupted Ca signaling in primary sensory neurons, including decreased endoplasmic reticulum (ER) Ca storage. This study examines potential causes and functional consequences of Ca store limitation after injury. METHODS: Neurons were dissociated from axotomized fifth lumbar (L5) and the adjacent L4 dorsal root ganglia after L5 spinal nerve ligation that produced hyperalgesia, and they were compared to neurons from control animals. Intracellular Ca levels were measured with Fura-2 microfluorometry, and ER was labeled with probes or antibodies. Ultrastructural morphology was analyzed by electron microscopy of nondissociated dorsal root ganglia, and intracellular electrophysiological recordings were obtained from intact ganglia. RESULTS: Live neuron staining with BODIPY FL-X thapsigargin (Invitrogen, Carlsbad, CA) revealed a 40% decrease in sarco-endoplasmic reticulum Ca-ATPase binding in axotomized L5 neurons and a 34% decrease in L4 neurons. Immunocytochemical labeling for the ER Ca-binding protein calreticulin was unaffected by injury. Total length of ER profiles in electron micrographs was reduced by 53% in small axotomized L5 neurons, but it was increased in L4 neurons. Cisternal stacks of ER and aggregation of ribosomes occurred less frequently in axotomized neurons. Ca-induced Ca release, examined by microfluorometry with dantrolene, was eliminated in axotomized neurons. Pharmacologic blockade of Ca-induced Ca release with dantrolene produced hyperexcitability in control neurons, confirming its functional importance. CONCLUSIONS: After axotomy, ER Ca stores are reduced by anatomic loss and possibly diminished sarco-endoplasmic reticulum Ca-ATPase. The resulting disruption of Ca-induced Ca release and protein synthesis may contribute to the generation of neuropathic pain.

Species and strain differences in rodent sciatic nerve anatomy: implications for studies of neuropathic pain.

Hindlimb pain models developed in rats have been transposed to mice, but assumed sciatic nerve neuroanatomic similarities have not been examined. We compared sciatic nerve structural organization in mouse strains (C57BL/6J, DBA/2J, and B6129PF2/J) and rat strains (Wistar, Brown Norway, and Sprague-Dawley). Dissection and retrograde labeling showed mouse sciatic nerve origins predominantly from the third lumbar (L3) and L4 spinal nerves, unlike the L4 and L5 in rats. Proportionate contributions by each level differed significantly between strains in both mice and rats. Whereas all rats had six lumbar vertebrae, variable patterns in mice included mostly five vertebrae in DBA/2J, mostly six vertebrae in C57BL/6J, and a mix in B6129PF2/J. Mice with a short lumbar vertebral column showed a rostral shift in relative contributions to the sciatic nerve by L3 and L4. Ligation of the mouse L4 nerve created hyperalgesia similar to that in rats after L5 ligation, and motor changes were similar after mouse L4 and rat L5 ligation (foot cupping) and after mouse L3 and rat L4 ligation (flexion weakness). Thus, mouse L3 and L4 neural segments are anatomically and functionally homologous with rat L4 and L5 segments. Neuronal changes after distal injury or inflammation should be sought in the mouse L3 and L4 ganglia, and the spinal nerve ligation model in mice should involve ligation of the L4 nerve while L3 remains intact. Strain-dependent variability in segmental contributions to the sciatic nerve may account in part for genetic differences in pain behavior after spinal nerve ligation.

Permeability of injured and intact peripheral nerves and dorsal root ganglia.

BACKGROUND: Nerve injury that produces behavioral changes of allodynia and hyperalgesia in animals is associated with electrophysiologic changes in dorsal root ganglion (DRG) cells. The introduction of drugs into the DRG or the peripheral nerve that alter calcium, sodium, or potassium channel activity may be of therapeutic benefit after nerve injury. For this reason, the authors sought to determine whether drugs that do not ordinarily cross the blood-nerve barrier will enter the DRG after intravenous or regional injection and to determine whether nerve injury alters drug access to DRGs or peripheral nerves. METHODS: Both intact and spinal nerve-ligated rats were injected with sodium fluorescein by intravenous, intrathecal, peri-DRG, perisciatic, and epidural routes. DRG, sciatic nerve, and spinal cord tissues were harvested and frozen, and histologic sections were analyzed quantitatively for tissue fluorescence. RESULTS: In both intact and nerve-injured animals, fluorescein accumulated in DRGs after intravenous, peri-DRG, and epidural injection. There was accumulation in the proximal portion of the ganglion after intrathecal injection. Minimal amounts of fluorescein were found in the sciatic nerve in intact animals after intravenous or perineural injection, but substantial amounts were found in some nerve fascicles in nerve-injured animals after both intravenous and perineural injection. There was almost no fluorescein found in the spinal cord except after intrathecal administration. CONCLUSIONS: In both intact and nerve-injured animals, fluorescein accumulates freely in the DRG after intravenous, epidural, or paravertebral injection. The sciatic nerve is relatively impermeable to fluorescein, but access by either systemic or regional injection is enhanced after nerve injury.

Painful nerve injury decreases resting cytosolic calcium concentrations in sensory neurons of rats.

BACKGROUND: Neuropathic pain is difficult to treat and poorly understood at the cellular level. Although cytoplasmic calcium ([Ca]c) critically regulates neuronal function, the effects of peripheral nerve injury on resting sensory neuronal [Ca]c are unknown. METHODS: Resting [Ca]c was determined by microfluorometry in Fura-2 AM-loaded neurons dissociated from dorsal root ganglia of animals with hyperalgesia to mechanical stimulation after spinal nerve ligation and section (SNL) at the fifth and sixth lumbar (L5 and L6) levels and from animals after skin incision alone (control group). Axotomized neurons from the L5 dorsal root ganglia were examined separately from adjacent L4 neurons that share the sciatic nerve with degenerating L5 fibers. RESULTS: After SNL, large (34 mum or larger) neurons from the L4 ganglion showed a 29% decrease in resting [Ca]c, whereas those from the L5 ganglion showed a 54% decrease. Small neurons only showed an effect of injury in the axotomized L5 neurons, in which resting [Ca]c decreased by 30%. A decrease in resting [Ca]c was not seen in neurons isolated from rats in which hyperalgesia did not develop after SNL. In separate experiments, SNL reduced resting [Ca]c in capsaicin-insensitive neurons of the L5 ganglion by 60%, but there was no change in neurons from L4. Resting [Ca]c of capsaicin-sensitive neurons was not affected by injury in either ganglion. SNL injury decreased the proportion of neurons sensitive to capsaicin in the L5 group but increased the proportion in the L4 group. CONCLUSIONS: Painful SNL nerve injury depresses resting [Ca]c in sensory neurons. This is most marked in axotomized neurons, especially the large and capsaicin-insensitive neurons presumed to transmit non-nociceptive sensory information.

Synovial cysts and the lithotomy position causing cauda equina syndrome.

We describe a case of cauda equina syndrome caused by synovial cysts and the lithotomy position. A transurethral resection of the prostate was performed under spinal anesthesia in the lithotomy position. We believe that this is the first case report of facet joint synovial cysts and the lithotomy position causing ischemic neurologic injury to the cauda equina. Other etiologies such as needle trauma, neurotoxicity, hematoma, and abscess were not evident. We believe that positioning the patient in the lithotomy position narrowed the cross-sectional area of the spinal canal in a patient with a coexisting critically stenosed lumbar spinal canal. The resultant mechanical pressure caused an ischemic compression injury to the cauda equina.

Intrathecal baclofen in pain management.

Baclofen is a GABA(B) agonist that is administered spinally via an implanted drug delivery device to treat spasticity. It has been shown to have powerful antinociceptive effects in experimental animal models at doses that produce little or no motor-blocking effects but has rarely been used as a spinal analgesic agent in patients without spasticity. Several studies have indicated that intrathecal baclofen provides relief of central pain in patients with spasticity. To date, only 3 studies have shown it to be effective in patients with peripheral nociceptive or neuropathic pain mechanisms. Combinations of baclofen and morphine or clonidine are more effective than each drug alone in clinical as well as animal studies.

Intrathecal baclofen: a useful agent in the treatment of well-established complex regional pain syndrome.

BACKGROUND AND OBJECTIVES: We present 2 case reports that illustrate that chronic intrathecal (IT) baclofen administration may be efficacious in treating patients with long-standing complex regional pain syndrome, type I (CRPS I) who have failed treatment with multiple drugs and procedures. CASE REPORTS: Both cases presented were women who developed CRPS I following multiple lower extremity surgeries. One patient had had symptoms for 5 years and had continued symptoms despite multiple sympathetic blocks, sympathectomy, spinal cord stimulation, and various medication trials. The other patient had had chronic lower extremity pain for 30 years and symptoms of CRPS for about 5 years. Her symptoms continued despite multiple sympathetic blocks, sympathectomy, and many medications. Neither patient had motor dysfunction (dystonia, tremors, spasticity) associated with their painful disorder. One patient experienced good control of pain, allodynia, and autonomic dysfunction with a combination of IT baclofen and clonidine after failing treatment with IT morphine. Baclofen alone produced intolerable side effects at the doses required to produce adequate analgesia. The other patient experienced long-term control of pain, allodynia, and autonomic symptoms with IT baclofen alone. CONCLUSIONS: IT baclofen appears to be an option for patients with intractable CRPS who have failed other modalities, including IT morphine.

Factors predicting short-term outcome of nerve blocks in the management of chronic pain.

In order to identify those chronic pain patients unlikely to improve from nerve blocks, preadmission questionnaires of 337 patients were studied and various pre-existing factors were analyzed against short term treatment results. Factors associated with significant reductions in treatment success (P less than 0.05) included: being injured at work, being out of work because of pain, receiving financial compensation, involvement in legal action, previous surgery for pain, long duration of pain, high pain severity ratings, frequent analgesic use and use of tranquilizers.