Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

Abstract

Chronic low back pain (LBP) is a debilitating condition associated with signs of axial and radiating pain. In humans with chronic LBP, opioids are often prescribed with varying outcomes and a multitude of side effects. Combination therapies, in which multiple pharmacological agents synergize to ameliorate pain without similar potentiation of adverse reactions, may be useful in improving therapeutic outcome in these patients. The SPARC-null mouse model of low back pain due to disc degeneration was used to assess the effects of opioid (morphine) and α 2-adrenergic agonist (clonidine) coadministration on measures of axial and radiating pain. The results indicate that systemic morphine and clonidine, coadministered at a fixed dose of 100 : 1 (morphine : clonidine), show a synergistic interaction in reversing signs of axial LBP, in addition to improving the therapeutic window for radiating LBP. Furthermore, these improvements were observed in the absence of synergy in assays of motor function which are indicative of side effects such as sedation and motor incoordination. These data show that the addition of low-dose systemic clonidine improves therapeutic outcome in measures of both axial and radiating pain. Combination therapy could be of enormous benefit to patients suffering from chronic LBP.

Analgesic synergy between opioid and α2‐adrenoceptors

“…If similar synergistic interactions also occur in undesired side effects, then the therapeutic benefits will be limited. While few preclinical studies have directly addressed this question (Tajerian et al ., ), clinical studies have indicated that side effects remain generally unchanged with drug combinations that enhance analgesia or decrease overall opioid requirement (Förster and Rosenberg, ; Paech et al ., ). Additional studies are necessary to fully characterize the impact of opioid–adrenoceptor agonist co‐administration on analgesia versus undesired side effects.…”

“…For example, despite an extensive co‐expression of MOP receptors and α 2 ‐adrenoceptors in locus coerulus neurons, electrophysiological recordings revealed only an additive interaction among these receptors (Stone and Wilcox, ). Although synergistic interactions are observed when drugs are administered systemically (Ossipov et al ., ; Tajerian et al ., ), there is little evidence suggesting that synergy occurs outside the spinal cord. Further studies are therefore necessary to explore the full potential of other routes of administration that are more practical than spinal delivery for the treatment of chronic pain.…”

“…or epidural drug delivery methods are not practical for most patients, a fact which represents an obstacle to the rapid translation of the preclinical knowledge summarized in this review. The antinociceptive synergy between morphine and clonidine is maintained when drugs are administered systemically, and side effects are not potentiated by the combination (Ossipov et al ., ; Tajerian et al ., ). As adrenoceptor agonists are already available and approved for systemic delivery, the preclinical findings suggest that they could be used in combination with opioids to obtain augmented analgesia.…”

Effects of Continuous Intravenous Infusion of Dexmedetomidine and Propofol on the Block and Postoperative Analgesic Characteristics of Sciatic Femoral Nerve Block

“…19 Aynı nöron üzerinde yerleşmiş α-2 adrenerjik ve opioid reseptörleri arasında bir kooperasyon mevcut olabilir, veya birbirinden bağımsız olarak G protein aktivasyonları ile intrasellüler mekanizmaları değiştirerek aditif veya sinerjistik etki gös-teriyor olabilirler. 20 Bununla beraber, α-2 adrenerjik reseptörler opioid sistemden bağımsız etki gösteriyor olabilir, çünkü α-2 adrenerjik agonistlerin antinosiseptif etkisi, opioid antagonisti olan naloksan varlığından etkilenmemektedir. 20 Yapılan çalışmalarda, gönüllülere ven içi olarak verilen deksmedetomidinin postoperatif analjezide ağrı ve opioid tüketimini azalttığı belirlenmiştir.…”

“…20 Bununla beraber, α-2 adrenerjik reseptörler opioid sistemden bağımsız etki gösteriyor olabilir, çünkü α-2 adrenerjik agonistlerin antinosiseptif etkisi, opioid antagonisti olan naloksan varlığından etkilenmemektedir. 20 Yapılan çalışmalarda, gönüllülere ven içi olarak verilen deksmedetomidinin postoperatif analjezide ağrı ve opioid tüketimini azalttığı belirlenmiştir. 13,21,22 Bizim çalışmamızda deksmedetomidin propofol ile karşılaştırıldığında, siyatik femoral sinir bloğunun postoperatif analjezik özellikleri üzerine istatistiksel olarak anlamlı etkileri olmamıştır.…”