Multi-target treatment of bone cancer pain using synergistic combinations of pharmacological compounds in experimental animals
-
Antti Pertovaara
In this issue of the Scandinavian Journal of Pain, González- Rodríguez and coworkers report about treatment of bone cancer pain using synergistic combinations of a dual enkephalinase inhibitor with various other drugs in experimental animals [1]. In the clinic, cancer, particularly that originating in the lung, breast and prostate, frequently metastasizes to bone, where it may cause pain, although not in all subjects or at all metastasized sites [2]. Bone cancer-induced pain may progress quickly from intermittent to continuous and further to breakthrough pain with episodes of extreme pain that occur spontaneously or that are induced e.g. by weight-bearing on the tumour-affected bones [3]. Additionally, bone cancer pain can be accompanied by mechanical hypersensitivity, due to which even gentle movements or touching the skin close to the tumour may induce strong pain [4,5]. These bone cancer-induced symptoms can severely reduce quality of life.
1 Experimental animal models in the study of mechanisms of bone cancer pain
Development of experimental animal models for the study of bone cancer pain has significantly advanced our understanding of underlying mechanisms. Behaviorally, animal models of bone cancer pain induce in the affected limb guarding and mechanical hypersensitivity mirroring continuous pain and tactile allodynia in the clinic [4]. In the bone of healthy control animals, sensory and sympathetic fibre innervation is most dense in the periosteum but also mineralized bone and marrow are innervated. Bone cancer induces sprouting of bone-innervating nerve fibres and the formation of neuroma-like features in periosteum [5]. Other peripheral changes that are likely to exert a role in bone cancer pain are upregulations of growth factors, cytokines and chemokines that are accompanied by pH changes and oxidative stress, all of which may influence excitability of sensory nerve fibre endings in the bone [3,5].
Among neurochemical and functional changes in the spinal cord dorsal horn of animals with bone cancer pain are an increased expression of a prohyperalgesic peptide dynorphin, increased neuronal activity, increased activation of astrocytes, and intense internalization of substance P (SP) receptors following innocuous mechanical stimulation of the affected limb [4]. Interestingly, inflammatory pain condition, such as that induced by complete Freund’s adjuvant, leads to spinal up-regulation of SP and calcitonin gene-related peptide (CGRP), two neuropeptides found in nociceptive neurons. Neuropathic pain condition, such as that induced by peripheral nerve injury, leads to spinal down-regulation of these two neuropeptides. In contrast, bone cancer pain has a distinct spinal mechanism that differs from those of inflammatory and neuropathic pain as indicated by the finding that bone cancer pain failed to influence SP or CGRP levels in the spinal cord [3].
2 Treatment of bone cancer pain
Therapy of bone cancer pain, particularly when it is induced by bone metastases, involves multiple complementary approaches that include eradication of tumour using chemotherapy and radiation therapy, surgical stabilization of painful bones, decreasing potentially pain-promoting loss of bone e.g. with bisphosphonates, and administration of various analgesic compounds such as nonsteroidal anti-inflammatory drugs and opioids [1,2-3]
3 Maximizing analgesic effect and minimizing side-effects with drug combinations
Unless eradication of cancer is successful, bone cancer and thereby bone cancer pain usually progresses and analgesic drugs need to be given for prolonged periods at increasing doses, due to which adverse effects of drugs provide a problem in the therapy of bone cancer pain. One approach to reduce side-effects and in parallel enhance pain-suppressive effects of analgesic compounds is to use combinations of drugs that reduce pain by acting on different targets and that have different, in the ideal case opposite, side-effects.
4 Enkephalinase inhibitors in treatment of bone cancer pain
Met-and Leu-enkephalin are endogenous compounds released tonically at an injured site and suppressing pain behaviour due to action on mu and delta opioid receptors [1]. Met- and Leu-enkephalin are quickly degraded by two endogenous enkephalinases and therefore, their analgesic action is only of brief duration. However, administration of a dual enkephalinase inhibitor reduces degradation of Met- and Leu-enkephalin and thereby enhances and prolongs their analgesic effects particularly at the injured area, where they are tonically released [1]. In their present experimental animal study on bone cancer pain, González- Rodríguez et al. report that a combination of the dual enkephalinase inhibitor PL265 with various other analgesic compounds acting on different targets produces synergistic analgesic effects. This allows using lower doses of each analgesic drug and thereby drug-induced side-effects are reduced [1].
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2016.09.011.
-
Conflicts of interest: The author declares no conflicts of interest
References
[1] González-Rodríguez S, Poras H, Menéndez L, Lastra A, Ouimet T, Fournié-Zaluski MC, Roques BP, Baamonde A. Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain. Scand J Pain 2017;14:25–38.Suche in Google Scholar
[2] Cherry NI. The assessment of cancer pain. In: Wall and Melzack’s textbook of pain. 5th ed. China: Elsevier; 2006. p. 1099–125.Suche in Google Scholar
[3] Halvorson KG, Sevcik MA, Ghilardi JR, Rosol TJ, Mantyh PW. Similarities and differences in tumor growth, skeletal remodeling and pain in an osteolytic and osteoblastic model of bone cancer pain. Clin J Pain 2006;22:587–600.Suche in Google Scholar
[4] Clohisy DR, Mantyh PW. Bone cancer pain. Cancer 2003;97:866–73.Suche in Google Scholar
[5] Lozano-Ondoua AN, Symons-Liguori AM, Vanderah TW. Mechanisms of cancer-induced bone pain. Neurosci Lett 2013;557:52–9.Suche in Google Scholar
© 2016 Scandinavian Association for the Study of Pain
Artikel in diesem Heft
- Scandinavian Journal of Pain
- Editorial comment
- Patients with chronic neck-pain after trauma do not differ in type of symptoms and signs, but suffer more than patients with chronic neck pain without a traumatic onset
- Observational study
- Chronic neck pain patients with traumatic or non-traumatic onset: Differences in characteristics. A cross-sectional study
- Editorial Comment
- Re-enforcing therapeutic effect by positive expectations of pain-relief from our interventions
- Original experimental
- Effect of expectation on pain assessment of lower- and higher-intensity stimuli
- Editorial comment
- Objective methods for the assessment of the spinal and supraspinal effects of opioids
- Topical review
- Objective methods for the assessment of the spinal and supraspinal effects of opioids
- Editorial Comment
- Multi-target treatment of bone cancer pain using synergistic combinations of pharmacological compounds in experimental animals
- Original experimental
- Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain
- Editorial comment
- Terminal cancer pain intractable by conventional pain management can be effectively relieved by intrathecal administration of a local anaesthetic plus an opioid and an alfa2-agonist into the cerebro-spinal-fluid
- Observational study
- Multimodal intrathecal analgesia in refractory cancer pain
- Editorial comment
- Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables
- Observational study
- Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables
- Editorial comment
- Why are some patients with chronic pain from anterior abdominal nerve entrapment syndrome (ACNES) refractory to peripheral treatment with neurectomy?
- Clinical pain research
- Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study
- Editorial comment
- Gain in functions before pain reduction during intensive multidisciplinary paediatric pain rehabilitation programme
- Clinical pain research
- Physical and occupational therapy outcomes: Adolescents’ change in functional abilities using objective measures and self-report
- Editorial comment
- Complex Regional Pain Syndrome (CRPS): High risk of CRPS after trauma in another limb in patients who already have CRPS in one hand or foot: Lasting changes in neural pain modulating systems?
- Clinical pain research
- The risk of pain syndrome affecting a previously non-painful limb following trauma or surgery in patients with a history of complex regional pain syndrome
- Editorial Comment
- Positive affect could reduce the impact of pain
- Original experimental
- The buffering role of positive affect on the association between pain intensity and pain related outcomes
- Editorial comment
- The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering – Lessons to be learned and relearned
- Clinical pain research
- The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering
- Editorial comment
- Invasive intervention for “intractable” Complex Regional Pain Syndromes (CRPS)?
- Educational case report
- Intrathecal management of complex regional pain syndrome: A case report and literature
- Observational study
- Item response theory analysis of the Pain Self-Efficacy Questionnaire
- Announcement
- Scandinavian Association for the Study of Pain (SASP): Annual Meeting 2017
Artikel in diesem Heft
- Scandinavian Journal of Pain
- Editorial comment
- Patients with chronic neck-pain after trauma do not differ in type of symptoms and signs, but suffer more than patients with chronic neck pain without a traumatic onset
- Observational study
- Chronic neck pain patients with traumatic or non-traumatic onset: Differences in characteristics. A cross-sectional study
- Editorial Comment
- Re-enforcing therapeutic effect by positive expectations of pain-relief from our interventions
- Original experimental
- Effect of expectation on pain assessment of lower- and higher-intensity stimuli
- Editorial comment
- Objective methods for the assessment of the spinal and supraspinal effects of opioids
- Topical review
- Objective methods for the assessment of the spinal and supraspinal effects of opioids
- Editorial Comment
- Multi-target treatment of bone cancer pain using synergistic combinations of pharmacological compounds in experimental animals
- Original experimental
- Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain
- Editorial comment
- Terminal cancer pain intractable by conventional pain management can be effectively relieved by intrathecal administration of a local anaesthetic plus an opioid and an alfa2-agonist into the cerebro-spinal-fluid
- Observational study
- Multimodal intrathecal analgesia in refractory cancer pain
- Editorial comment
- Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables
- Observational study
- Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables
- Editorial comment
- Why are some patients with chronic pain from anterior abdominal nerve entrapment syndrome (ACNES) refractory to peripheral treatment with neurectomy?
- Clinical pain research
- Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study
- Editorial comment
- Gain in functions before pain reduction during intensive multidisciplinary paediatric pain rehabilitation programme
- Clinical pain research
- Physical and occupational therapy outcomes: Adolescents’ change in functional abilities using objective measures and self-report
- Editorial comment
- Complex Regional Pain Syndrome (CRPS): High risk of CRPS after trauma in another limb in patients who already have CRPS in one hand or foot: Lasting changes in neural pain modulating systems?
- Clinical pain research
- The risk of pain syndrome affecting a previously non-painful limb following trauma or surgery in patients with a history of complex regional pain syndrome
- Editorial Comment
- Positive affect could reduce the impact of pain
- Original experimental
- The buffering role of positive affect on the association between pain intensity and pain related outcomes
- Editorial comment
- The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering – Lessons to be learned and relearned
- Clinical pain research
- The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering
- Editorial comment
- Invasive intervention for “intractable” Complex Regional Pain Syndromes (CRPS)?
- Educational case report
- Intrathecal management of complex regional pain syndrome: A case report and literature
- Observational study
- Item response theory analysis of the Pain Self-Efficacy Questionnaire
- Announcement
- Scandinavian Association for the Study of Pain (SASP): Annual Meeting 2017
