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Pain


Table 1: Conversion Ratios Between Routes of Administration for Commonly Used Opioids and Baclofen


Agent Morphine


Oral Parenteral Epidural Intrathecal Hydrophilicity (mg) (mg) 300 100


(mg) 10


Hydromorphone 40–60 10 Meperedine Fentanyl Sufentanil Baclofen


1 2


3,000 1,000 – – 1


0.1 –


100 0.1


0.01 –


(mg) 1


0.2 10


0.01


0.001 0.005


High


Intermediate Low Low Low High


Note: ratios between opioids and baclofen do not represent equianalgesic doses.


neuropathic and mixed pain characteristics in available studies. There are several retrospective studies of small size documenting the potential benefits of intrathecal opioids in complex regional pain syndrome (CRPS),20,21


but randomized prospective studies are lacking.


A major advantage of intrathecal administration of opioids lies in the low equianalgesic dose compared with oral opioids (roughly 300:1 for both morphine and hydromorphone). While this tends to result in fewer opioid-related systemic adverse effects, prospective studies have noted common adverse effects to include sedation, constipation, confusion, and hypogonadism. Complications related to pumps and their surgical implantation (e.g. catheter migration and kinking, infection, need for surgical revision) have been reported to occur in between 6 and 25 % of patients.13,14,22


Catheter tip granuloma formation is a serious and potentially devastating complication and a controversial topic. Animal studies suggest that granuloma formation is directly correlated to increasing opioid dose and concentration, although a recent retrospective study in humans refutes this.23,24


It has been suggested that concomitant administration of


intrathecal clonidine is protective against granuloma formation, although the evidence for this is weak and the possible mechanism for this purported protection remains unclear.24,25


Table 1 summarizes the conversion ratios between routes of administration for commonly used opiods and baclofen.


Gamma-aminobutyric Acid Agonists Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter widely distributed throughout the nervous system. Activation of GABA receptor subtypes GABA-A and GABA-B results in an intracellular influx of chloride ions, hyperpolarizing the neural cell membrane and decreasing excitability. The GABA-A receptor exists as a ligand-gated (ionotropic) chloride channel, whereas the GABA-B receptor is a G-protein-linked (metabotropic) complex whose activation results in amplification of current through potassium channels. GABA-B receptors are found both pre- and post-synaptically. Pre-synaptic activation results in decreased excitatory neurotransmitter release, while post-synaptic activation leads to membrane hyperpolarization.26


Although some


literature refers to a third receptor (GABAC), the close relation of this receptor to GABA-A in sequence, structure, and function has caused the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology to recommend that these receptors be referred to as part of a sub-family of GABA-A.27


Common GABA-A receptor agonists include ethanol, barbiturates, benzodiazepines, zolpidem, and eszopiclone, but only midazolam


156


has been shown to be efficacious in treating neuropathic pain when administered intrathecally. Midazolam is currently a fourth-line intrathecal treatment for chronic pain.28


Spinal GABA and


alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in the mechanisms of neuropathic pain after nerve injury. Using a rat model, Lim et al.29


demonstrated


that spinal GABA-A receptor activation by intrathecal midazolam attenuated the expression and function of spinal AMPA receptors in rats following peripheral nerve injury, ultimately reducing thermal hyperalgesia and mechanical allodynia compared with a control group.


In a randomized trial, Dureja et al.30 studied the effects of 2 mg intrathecal


midazolam with and without epidural methylprednisolone when administered to patients suffering from lumbosacral post-herpetic neuralgia. Not only did the group receiving intrathecal midazolam monotherapy report lower pain scores and allodynia for up to 12 weeks post-injection, the combination was found to behave synergistically. In another clinical trial, Borg and Krijnen31


treated four patients with chronic benign neurogenic


and musculoskeletal pain refractory to conventional analgesics with continuous infusions of up to 6 mg/day of intrathecal midazolam in combination with clonidine or morphine. In all four patients, long-term infusion therapy resulted in nearly complete abolishment of pain symptoms.


Inasmuch as dorsal horn GABA receptor inhibition has been demonstrated to play an important role in neuropathic pain following nerve injury,32 elucidation of the inhibitory mechanisms has led researchers to postulate that the addition of acetazolamide and its inhibition of carbonic anhydrase would enhance the efficacy of GABAergic inhibition in the context of neuropathic pain. Asiedu et al.33


of acetazolamide and midazolam acts synergistically to reduce neuropathic allodynia after peripheral nerve injury.


Animal studies assessing the toxicity of intrathecal midazolam have yielded conflicting results, with approximately half reporting neurotoxicity.34 Deleterious effects have been observed with as little as a single dose, but many studies have shown no pathologic effects after continuous usage, prompting some to conclude that intrathecal midazolam is no more neurotoxic than normal saline.35,36


In a cohort study evaluating the effects


of adding 2 mg of midazolam to local anesthetic in 1,100 patients undergoing spinal anesthesia, Tucker et al.37


post-operative neurologic symptoms over local anesthetic alone.


Fewer GABA-B agonists are commercially available, but baclofen has shown to be efficacious when given intrathecally to treat spasticity, CRPS, and central pain secondary to stroke or spinal cord injury (SCI). Whereas intrathecal baclofen is currently a first-line agent for the treatment of spasticity secondary to SCI, multiple sclerosis, and other disorders, recent studies have been able to distinguish between the analgesic and spasmolytic properties. These effects are not reversed by the opioid antagonist naloxone, suggesting that GABAergic analgesia occurs via a separate pathway not shared by endogenous opiates. Baclofen is currently considered a fourth-line treatment for chronic pain.28


In a randomized, double-blind trial, seven women with CRPS were given intrathecal bolus injections of baclofen 25, 50, or 75 µg, or saline.38 statistical difference was found between the 25 µg and saline injections,


No US NEUROLOGY found no increase in


found that spinal co-administration


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