Chloride Regulation in the Pain Pathway

This paper describes a prospective, double blind, randomised and dummy-controlled trial in 28 patients with chronic mechanical low back pain presenting to the York Pain Clinic. The therapeutic effects of epidural methyl prednisolone (80 mg) were compared with intrathecal midazolam (2 mg). All the patients had pain for a considerable length of time (range: 1–35 years) and all had received previous treatments which had failed. The two groups of patients were comparable in terms of pain duration, demography, extent of disability, anxiety and depression and pain locus of control. The pain was assessed before and for 2 months after treatment using the short form McGill Pain Questionnaire as well as visual analogue and verbal rating scales for sensory and affective components of their pain experience; patients also completed a pain diary. Both treatments caused a similar improvement in one-half to three-quarters of the patients for 2 months in patterns of activity and sleep as well as in the sensory and affective components of the pain. However, although the improvement in the two groups was similar, all the patients treated with steroid were either taking more or the same amount of self-administered analgesic medication after their treatment, whereas between one-third and one-half of the midazolam-treated patients took less medication during the 2 month follow-up period. We conclude that intrathecal midazolam is an effective treatment for chronic mechanical low back pain. The mechanism responsible for this effect is discussed.

Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study.

Animal models of analgesia peripheral mediators of pain non-steroidal anti-inflammatory drugs and pain the sympathetic nervous system and pain excitability blockers - anticonvulsants and low concentration local anaesthetics in the treatment of chronic pain tachykinins - central and peripheral effects growth factors and pain mechanisms of central hypersensitivity novel modulators in nociception pharmacological studies of nociceptive systems using the C-Fos immunohistochemical technique molecular aspects of opioid receptors opioid pharmacology of acute and chronic pain opioid problems, and morphine metabolism and excretion inhibitory neurotransmitters and nociception role of descending noradrenergic and serotoninergic pathways in the modulation of nociception neonatal pharmacology of pain.

The Pharmacology of Pain

https://www.jpsmjournal.com/article/S0885-3924(00)00204-9/pdf

Evidence-Based Review of the Literature on Intrathecal Delivery of Pain Medication

Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans).

Adjuvants to local anesthetics: Current understanding and future trends

The electrical current thresholds for pain (ECTP) in the skin of the neck and tail were measured in rats with chronically implanted lumbar subarachnoid catheters The effects of a benzodiazepine antagonist and a gamma-aminobutyric acid (GABA) antagonist on the analgesic effects of equivalent doses of midazolam, fentanyl, and ketocyclazocine were studied These were the minimum doses producing maximal segmental analgesia when given intrathecally (ie, they all caused a significant and maximum increase in ECTP in the tail, which was similar for all three drugs, but no significant change in the ECTP in the neck) Flumazenil (Ro 15-1788) administration caused a parallel shift to the right of the dose-response curve for midazolam spinal analgesia Segmental analgesia following midazolam was also significantly attenuated (P less than 005) when the selective GABA antagonist bicuculline was given intrathecally at the same time as midazolam The highest dose of bicuculline used (50 pmol) caused no significant attenuation of the segmental analgesic effects of either ketocyclazocine or fentanyl The authors concluded that the segmental analgesia produced by intrathecal midazolam is mediated by the benzodiazepine-GABA receptor complex that is involved in other benzodiazepine actions

On the Mechanism by Which Midazolam Causes Spinally Mediated Analgesia

The effects of intrathecal midazolam and fentanyl on electrical current threshold for pain were measured using stimulating electrodes in the neck and tail of rats with chronically implanted lumbar subarachnoid catheters This involved the measurement of the minimum current (50 Hz 2 ms pulses 0-5 mA), which made the rat squeak when applied alternately to electrodes at each skin site The responses measured in milliamperes were expressed as a number of times control readings Equieffective doses of both midazolam and fentanyl produced a significant increase in electrical threshold for pain in the tail (mean +/- SEM 314 +/- 051 and 289 +/- 035: P less than 005; Wilcoxon sum rank test) in the absence of any change in the neck (mean +/- SEM 128 +/- 013 and 096 +/- 012, NS), thus demonstrating a spinal effect Fentanyl caused a significant simultaneous increase in tail flick latency (mean +/- SEM 678 +/- 201%, P less than 005), but midazolam did not (mean +/- SEM 422 +/- 276%, NS) Intraperitoneal injections of naloxone (025 mg/kg) blocked the response to fentanyl in both tests and did not affect the response to midazolam Intraperitoneal flumazenil (5 mg/kg) blocked the midazolam antinociceptive effect but did not affect the response to fentanyl in either test Tail withdrawal in response to non-noxious stimulation was preserved in all animals with spinal analgesia, indicating that myelinated afferent and efferent pathways were still functioning Righting reflex, coordination, motor power, and alertness were also preserved in the presence of both drugs Both drugs caused spinally mediated antinociceptive effects that were qualitatively different

C. S. Goodchild

Papers

On the Mechanism by Which Midazolam Causes Spinally Mediated Analgesia

Intrathecal midazolam and fentanyl in the rat: evidence for different spinal antinociceptive effects.