Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs. inflammatory pain

Abstract

Pain is the cancer related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed. A critical question is how closely this model mirrors human bone cancer pain. In the present study we show that, as in humans, pain-related behaviors are diminished by systemic morphine administration in a dose dependent fashion that is naloxone-reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model, the doses of morphine required to block bone cancer pain-related behaviors were ten times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freund's adjuvant (CFA) (1-3mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer vs. inflammatory pain. These results indicate that this model may be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.

Advances in the therapy of cancer pain: from novel experimental models to evidence-based treatments

“…Morphine analgesia, also, does not affect limb use during forced ambulation, which is decreased (as expected) in the bone cancer pain model (66). Only very high doses (40 mg/kg) produced some slight amelioration, consistent with other observations, as well (37). This may help explain the fact that pain with activity or movement in humans, suffering from metastatic bone disease, may often be resistant to analgesic therapy with opioids or require high doses for suppression.…”

“…The correlation between anatomical progression and behavioral manifestations of pain, as well as similarities in the relative potency of treatments needed to suppress pain, indicate also the fact that this model simulates reliably several features of the clinical disease in humans. With regards to the latter, it has been shown that both the pain behavior induced in the mouse model of bone cancer pain, as well as the clinical pain in humans with bone metastases, are equally poorly responsive to opioids, compared to inflammatory pain (37). These observations validated the mouse metastatic bone pain model as adequate to elucidate mechanisms responsible for bone cancer pain, as well as the pertinent pharmacology, which may guide the development of new drugs to fight this type of pain (38).…”

Regional Anesthesia and Pain

“…This dose range of morphine is similar to that previously reported as being effective in blocking bone cancer pain-related behaviour in a mouse bone cancer pain model. 18,19 The effects of morphine were antagonized completely in response to naloxone, and the effects of the α-2 agonists were completely antagonized by idazoxan. These data support the concept that the action of morphine is mediated via activation of naloxone-sensitive opioid receptors, and that the effects of α-2 agonists are mediated via activation of idazoxan-sensitive α-2 receptors.…”

“…17 It has been reported that systemic administration of morphine produces an analgesic effect in this model, although the potency of morphine appears to be lower in the bone cancer pain model compared to the inflammatory pain model. 18,19 This suggests the existence of a different mechanism underlying bone cancer pain vs inflammatory pain. In the present study, the authors investigated the analgesic effects of ip administered α-2 receptor agonists dexmedetomidine and clonidine, NMDA receptor antagonists MK801 and ketamine, and the NAAG peptidase inhibitor ZJ-43, and compared the analgesic effect of these drugs with that of morphine in an animal model of bone cancer pain.…”

IL-4, JAK-STAT signaling, and pain

“…There are many models but in general they can be attributed to three main pain groups according to their etiology: inflammatory, cancer, and neuropathic pain. Several drugs such as opioids, [1][2][3] nonsteroidal anti-inflammatory drugs (NSAIDs), 4,5 IL-1 receptor antagonist, 6 or antibodies, e.g., anti-nerve growth factor (NGF) 7 and anti-tumor necrosis factor (TNF)-α, 8 were studied in cancer pain models showing different efficacy. In neuropathic pain also opioids, [9][10][11] purinergic receptor antagonist, 12 and enkephalindegrading inhibitors 13 have been tested.…”