GAINING ON PAIN: AN ONCOLOGIST S APPROACH Philip J. Bergman DVM, PhD, DACVIM (Oncology) Bedford Hills, NY

Transcription

1 GAINING ON PAIN: AN ONCOLOGIST S APPROACH Philip J. Bergman DVM, PhD, DACVIM (Oncology) Bedford Hills, NY INTRODUCTION Pain is unfortunately a common sequela in human cancers (~25-50%) and is extremely common in advanced and/or terminal human cancers (~75-95%). The exact percentages of veterinary cancer patients experiencing pain is poorly understood due to the dearth of investigations in this area to date. A recent PubMed search of human cancer pain returned over 67,000 citations, whereas a similar search on companion animals resulted in only ~ 300 citations, with the vast majority of these not having pain as a primary specific endpoint of investigation (e.g. CT findings in dogs and cats with TMJ disorders ). Thankfully, investigations into the mechanisms of companion animal cancer pain have begun within the last 10 years and are now beginning to appear in the veterinary literature, but far more investigations are desperately needed. Until then, we are forced to extrapolate information from the human side, which may or may not fully translate into our companion animal patients. Even if these human studies are fully extrapolated, it is highly likely a fair statement that we currently under-appreciate and/or poorly detect pain in companion animal patients with cancer. This may be because we may: 1) Focus more on the treatment than the pain (and forget that some cancer treatments temporarily cause pain in of themselves), 2) Poorly assess pain, and dogs/cats can have an innate ability to hide pain and disease, 3) Poorly teach our clients and our staff how to assess pain in their pets, 4) Have a variable understanding of the possible drugs and other pain relief techniques and 5) Have a limited appreciation that many different tumors are significantly associated with pain. Therefore, we also likely sub-optimally treat the pain being experienced in our companion animal patients with cancer. As this pain significantly affects quality of life and furthermore has important secondary physiologic sequelae, it is important that we have as a priority to aggressively and appropriately detect and treat cancer-associated pain in our patients. GENERAL APPROACH While every veterinary patient with cancer is different, the general approach one can take specifically for their pain management is quite similar. It is generally centered around the following large aspects: 1) Listen to the owner and ask open-ended questions around painassociated behaviors at home, 2) Incorporate a pain evaluation into your standard physical examination, 3) Determine and deliver the best treatment(s), often recognizing this requires a multimodal approach and 4) Repeat by going back to #1, as the management of a veterinary cancer patient s pain will be fluid and continually need to evolve over time based on the success or failure of that cancer treatment and concurrent pain treatments. While any tumor type may potentially cause pain, the tumor types which are most commonly associated with pain in order of descending severity are primary and metastatic bone tumors, inflammatory mammary carcinoma, oropharyngeal or nasal tumors especially with bony destruction, ulcerative and/or invasive skin tumors, CNS tumors (especially extradural), brachial plexus tumors, prostate and genitourinary tumors, intra-thoracic or intra-abdominal tumors, invasive and/or large soft tissue sarcomas and disseminated intra-cavitary tumors. It

2 is also worthy to note that in addition to the inherent pain associated with the above tumors, iatrogenic pain can be associated with the various treatments of cancer. This is most commonly and severely associated with surgical extirpation and external beam radiation, but can also temporarily be noted with chemotherapy and some of the newer rationally targeted therapeutics such as TKI s (tyrosine kinase inhibitors). Thankfully, many of the newer radiation modalities (e.g. CyberKnife, GammaKnife and other stereotactic methods) more precisely target cancerous tissue and minimize normal tissue dose, which reduces, but does not eliminate, the pain secondary to these radiation treatments. The behaviors of veterinary cancer patients that can be associated with pain include decreased appetite and/or activity, changes in attitude, increased hiding, increased respirations or overt panting, poor self-grooming, adverse/aversion responses to touching and/or palpation of the affected area, self-trauma, changes in facial expressions and changes in urination and/or defecation. It is important to note that vocalizations are seen rarely in response to chronic pain in dogs and cats and we further have a duty to inform our clients of this since this is not intuitive for the lay public. That said, cats may have changes in their meows or may hiss or purr when experiencing cancer-associated pain, whereas dogs may display grunting and/or whining as their methodology of vocalization secondary to significant cancer pain. The physiologic parameters noted in cancer-associated pain may include tachypnea, tachycardia, pupil dilation and increased blood pressure and/or body temperature. TREATMENT Tumor-directed Therapy The most rational strategy for managing pain in companion animal patients with cancer is to whenever possible treat the underlying tumor causing the pain. When indicated, this most quickly and least expensively is through surgical removal. When local treatments are indicated and surgery is not an option due to logistical, financial and/or emotional constraints, radiation is often a next best local treatment option. For those tumors which are systemic and/or likely to metastasize, then chemotherapy and/or rationally targeted therapies (e.g. TKI s, melanoma vaccine, etc.) are typically indicated. In those situations whereby the tumor is both locally aggressive and has a high propensity to metastasize, then combinations of local (ie Sx or RT) and systemic (ie chemo, TKI s, melanoma vaccine) treatment would be indicated to best treat the tumor and therefore most effectively reduce the patient s cancerassociated pain. Pharmacologic Therapies The pharmacologic therapy of pain is also often utilized for the treatment of cancerassociated pain as well as cancer treatment-associated pain. A general approach to the management of cancer pain through various analgesics which has worked generally well over time is the 1986 version of the WHO (World Health Organization) pain ladder. Step 1

3 of the ladder is for mild pain and utilizes a non-opioid (e.g. an NSAID or similar non-opioid) with an adjuvant non-opioid when necessary (see possible adjuvant analgesics outlined below). Step 2 of the ladder is for patients with moderate pain and combines those treatments used in step 1 alongside a low dose opioid. Step 3 of the ladder is for patients with severe pain and combines step 1 treatments with a regular dose opioid. Importantly, one should not routinely utilize two products belonging to the same category and/or mechanism of action simultaneously. For the last 25 years, this 3-tiered ladder system has worked well, but with the advent of newer analgesic treatments, a 4-tier ladder is being used more and more frequently in the treatment of human cancer-associated pain. Step 4 in this new system incorporates all the treatments used in steps 1, 2 and 3 and then also utilizes one or more treatments such as spinal stimulators, epidurals, nerve blocks, patient-assisted pain pumps, etc. The other unique aspect to the 4-tier system is that instead of unidirectional moving up the ladder steps, one may navigate the ladder bi-directionally depending on the type, level and chronicity of the pain being experienced by the patient (ie step UP or step DOWN as needed). These modifications to the original 3-step WHO ladder are very much not intended to advise against or negate the use of the original ladder, but more importantly are meant to be an upgrade or an evolution of the incredibly helpful original ladder. Graphical representations of the 3 and 4-tier pain ladders will be presented in the lecture. The WHO ladder also makes 5 extremely simple recommendations for the practitioner to ensure the therapeutics chosen have the greatest chance for success. These simple recommendations are as follows: 1) Use oral analgesics whenever possible (unfortunately some recent data in dogs suggests oral opioids at standard doses may not equate to effective plasma concentrations), 2) Regular intervals of analgesics are imperative, 3) Analgesic dosing should be individualized to the patient, 4) The scale and breadth of analgesic use should match the patient s level of pain and 5) Analgesics should be prescribed and described in detail for the medical staff and owner (in hospital and at home use, respectively). Pharmacologic Therapy Categories Non-Opioids (NSAIDs & Acetaminophen) NSAID s are excellent first line analgesics for cancer pain. All NSAIDs are most likely equally efficacious analgesics, but only piroxicam and deracoxib have been described to date to have potentially anti-cancer benefits as well. Cox-2 selective NSAIDs appear to have less GI side effects, but equal hepatic and/or renal side effects to more Cox-1 selective NSAIDs. Use of acetaminophen in cats continues to be contraindicated and concurrent use of NSAIDs and corticosteroids is contraindicated across species. Robenacoxib and meloxicam use in cats is currently FDA-approved for postoperative short term analgesia, whereas mildly and moderately longer term use has been described in the EU, respectively. Opioids Opioids are typically indicated for moderate to severe pain and are commonly used as part of a multimodal approach outlined in the aforementioned cancer pain ladder. Side effects can be significant and include vomiting, diarrhea, sedation, dysphoria (esp northern breeds and cats) and with chronic use, constipation and hyporexia. Even though very few studies have been performed investigating the efficacy and/or toxicity of opioids in

4 dogs or cats for chronic cancer pain, the most commonly utilized agents are oral butorphanol/codeine/tramadol/morphine, sublingual buprenorphine in cats or transdermal fentanyl. Oral butorphanol is a mixed mu antagonist and kappa agonist with a relatively short duration of analgesia (but long duration of sedation) and is therefore NOT routinely recommended for chronic cancer pain. Weak opioids such as codeine and/or tramadol may be useful for mild cancer pain. Tramadol has the advantage of being better tolerated in people compared to other opioids with similar analgesic potency. Tramadol also has norepi and serotonin reuptake inhibition, so it must be carefully utilized in patients already on serotonin reuptake inhibitors (e.g. fluoxetine, paroxetine, sertraline, trazadone, etc.) to thereby prevent serotonin syndrome. Buprenorphine is a partial mu agonist & antagonist, which when given by an oral transmucosal route is well tolerated in cats and is mildly to moderately effective for treating breakthrough pain. Mu agonists such as morphine, hydromorphone, oxymorphone and fentanyl are the best agents for moderate to severe chronic cancer pain. Unfortunately, a large percentage of dogs achieved sub-therapeutic plasma concentrations when fentanyl patches were investigated in a recent paper, and cats do not convert codeine to its active form so it is not recommended for use in cats. A new liquid transdermal topical fentanyl product from Elanco (Recuvyra ) appears to offer more consistent dosing and therapeutic concentrations for postoperative orthopedic analgesia in dogs, but no studies have been reported to date using it off label for cancer pain. Methadone is being used more commonly for human chronic cancer pain due to its mu agonist and NMDA antagonist properties, alongside reduced side effects and costs. Adjuvant analgesics these are a diverse group of agents with a primary use other than analgesia but usefulness in painful situations. These include corticosteroids, NMDA antagonists such as amantadine or ketamine, NK1 antagonists such as Cerenia, tricyclic antidepressants such as fluoxetine, anticonvulsants such as gabapentin, local anesthetics such as lidocaine or mexiletine, calcitonin, radiopharmaceuticals like strontium 89 or samarium 153, bisphosphonates like pamidronate, α2 agonists such as medetomidine, muscle relaxants, topical agents such as lidocaine and capsaicin, benzodiazepines, duralactin, Adequan, etc. The use of adjuvant analgesics is strongly recommended with neuropathic pain due to this type of pain being comparatively less sensitive to opioids. Furthermore, consistent use of adjuvant analgesics in patients with chronic cancer pain may enable reduced dosing of other analgesics and/or allow the clinician to less quickly need to take steps up the aforementioned pain ladder. Non-Pharmacologic Therapies A variety of adjunctive non-pharmacologic therapies for pain is available and appears to be potentially increasingly more important in the multi-modal treatment of cancer-associated pain. These modalities include acupuncture, rehabilitation therapies (such as hydrotherapy, massage, stretching, superficial cold or heat therapy, etc.), electrical nerve stimulation, pulsed magnetic field therapy, cold laser therapy, ultrasound, etc. These modalities should not be used in the place of analgesics, but may complement the benefits seen with standardof-care analgesics. New Analgesics on the Horizon?

5 New molecular-based analgesics are currently an extremely hot research topic. Items which may have clinical promise in the future include anti-ngf (nerve growth factor) monoclonal antibodies, intrathecal substance P, cannabinoid receptor agonists, T-type calcium channel blockers, endomorphins (natural mu ligands) and opioid peptide esters. Can Analgesics Promote Cancer? While this issue is not an intuitive primary concern, it is worth reviewing that some analgesics may be cancer-promoting. Fentanyl has been found to promote growth of a number of cancer cell lines in vitro. Similarly, numerous opioids have been found to stimulate angiogenesis through human endothelial cell proliferation. Furthermore, cancers of the larynx, esophagus, lung, stomach and bladder have as a risk factor the chronic use of opium. Some of the very newest ion channel-based analgesics target the same ion channels involved in tumorigenesis. For now the use of analgesics when indicated easily trumps any worries in current cancer patients, but more importantly this author felt it was worth highlighting this issue to promote a dialogue about the possible molecular and cellular effects of chronic analgesic use in non-cancer patients. Cases with various types of cancer pain and the strategies for their treatment will also be presented at the lecture. (1-15)References 1. Macfarlane PD, Tute AS, Alderson B. Therapeutic options for the treatment of chronic pain in dogs. J Small Anim Pract 2014 January Martinez SA, Wilson MG, Linton DD, Newbound GC, Freise KJ, Lin TL et al. The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study. J Vet Pharmacol Ther 2013 December Gearing DP, Virtue ER, Gearing RP, Drew AC. A fully caninised anti-ngf monoclonal antibody for pain relief in dogs. BMC Vet Res 2013;9: Brown DC, Agnello K. Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 2013 November;119(5): Teixeira RC, Monteiro ER, Campagnol D, Coelho K, Bressan TF, Monteiro BS. Effects of tramadol alone, in combination with meloxicam or dipyrone, on postoperative pain and the analgesic requirement in dogs undergoing unilateral mastectomy with or without ovariohysterectomy. Vet Anaesth Analg 2013 August Beckman B. Anesthesia and pain management for small animals. Vet Clin North Am Small Anim Pract 2013 May;43(3): Morgaz J, Navarrete R, Munoz-Rascon P, Dominguez JM, Fernandez-Sarmiento JA, Gomez-Villamandos RJ et al. Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. Res Vet Sci 2013 August;95(1): Lee SK, Dawson J, Lee JA, Osman G, Levitin MO, Guzel RM et al. Management of cancer pain: 1. Wider implications of orthodox analgesics. Int J Gen Med 2014;7:49-58.

6 9. Mearis M, Shega JW, Knoebel RW. Does Adherence to National Comprehensive Cancer Network Guidelines Improve Pain-Related Outcomes? An Evaluation of Inpatient Cancer Pain Management at an Academic Medical Center. J Pain Symptom Manage 2014 January Towler P, Molassiotis A, Brearley SG. What is the evidence for the use of acupuncture as an intervention for symptom management in cancer supportive and palliative care: an integrative overview of reviews. Support Care Cancer 2013 October;21(10): Mercadante S. Cancer pain. Curr Opin Support Palliat Care 2013 June;7(2): Santini D, Lanzetta G, Dell'Aquila E, Vincenzi B, Venditti O, Russano M et al. 'Old' and 'new' drugs for the treatment of cancer pain. Expert Opin Pharmacother 2013 March;14(4): Looney A. Oncology pain in veterinary patients. Top Companion Anim Med 2010 February;25(1): Gaynor JS. Control of cancer pain in veterinary patients. Vet Clin North Am Small Anim Pract 2008 November;38(6): , viii. 15. Lester P, Gaynor JS. Management of cancer pain. Vet Clin North Am Small Anim Pract 2000 July;30(4):951-66, ix.