With the United States in the midst of an opioid abuse crisis, cancer pain remains challenging for patients and their prescribers treating the burden of this disease. Clinicians have many legal restrictions when prescribing opioids, and some patients with cancer are hesitant to use this class of drugs because of the stigma of potential addiction.1

Cancer pain is just 1 of the many disease-related issues arising in these patients. An estimated 14 million patients with cancer reside in the United States, and about 40% of those are afflicted with associated pain.2 The treatment paradigm is slowly shifting toward a multimodal approach (ie, anticonvulsants, antidepressants, and nonsteroidal anti-inflammatory drugs [NSAIDs]), but opioids remain the agent of choice for cancer pain treatment.

Epidemiology
In the general population, when patients experience pain, it is usually the result of biological processes or injury. However, cancer pain is unique to those who are affected by either its manifestations or treatments. As a tumor enlarges, it can damage or exert pressure on nerve endings within the surrounding affected area. Additionally, certain types of cancer cells and tumors can release damaging or irritating chemicals that result in pain, such as bradykinin, endothelin-1, nerve growth factor, and tumornecrosis factor alpha.3 If cancers or tumors are not solely responsible for inducing pain, many patients experience discomfort related to their cancer treatment (eg, chemotherapy, radiation, and surgery). Patients have reported different types of pain, including mixed, neuropathic, or nociceptive, over the progression of their disease (figure 1).4 Nociceptive pain is pain caused by stimuli or tissue damage that has the potential to cause additional damage, whereas neuropathic pain is characterized by damage or dysfunction of the nervous system.5



Treatment 
Pain treatment should be individualized based on causes, characteristics, clinical condition, and patient goals, according to the European Society for Medical Oncology guidelines (figure 2).6,7 Patients’ pain intensity, signs, and symptoms should dictate treatment decisions.6 Pain may present as somatic pain, which can be related to disease manifestations, such as metastatic bone cancer and skeletal muscle inflammation. Standards for the treatment of somatic pain include acetaminophen, NSAIDs, and skeletal muscle relaxants. Visceral pain is associated with internal organs and can be related to organ compression or tumor infiltration. Neuropathic pain can arise from nerve damage, because of cancer treatment-related complications and tumor infiltration. Based on the suspected pathophysiology and pharmacotherapy, anticonvulsants (gabapentin and pregabalin), antidepressants (duloxetine and tricyclic antidepressants), and NSAIDs, can be used to target and ease disease-related suffering.6,8



Prolonged opioid use causes increased risk and incidence of opioid-induced constipation (OIC) and opioid-induced neurotoxicity (OIN). OIC has been shown to significantly reduce quality of life and has proved challenging to treat.9 Symptoms of OIN include hallucinations, hyperalgesia, and myoclonus, which can be severe but managed via opioid rotation and rehydration as deemed appropriate.10 Concomitant medications during cancer treatment, including possible cytochrome P450 enzyme inhibitors, may complicate treatment by further inducing opioid toxicity or decreasing analgesic effects through drug-drug interactions.11 Some patients at risk of developing opioid use disorders may be asked to participate in regular pain management consults and can be paired with multidisciplinary teams. These teams are formed according to the patient’s specific needs and can aid in psychological and social aspects of OUD to prevent further opioid dependence through education.12

New on the Horizon 
Opioids continue to be first-line therapy for moderate to severe pain in patients with cancer, despite their undesirable adverse effects.6 Neuropathic-targeted treatments continue to be at the forefront of cancer pain management and are the focus of new and improved drug regimens. Receptors, such as melatonin receptors type 1 and 2, and newer agents, such as the cannabinoids, may be prospective advances in the treatment of neuropathic pain. Medications such as cannabidiol, melatonin, quetiapine, have had their treatment roles expanded.13

Conclusion 
Unrelenting cancer pain can be devastating. With the United States in the grips of an opioid crisis, substance abuse must not cloud the needs of patients with cancer who are genuinely seeking relief from pain and suffering. It has been shown that these patients are far less likely to exploit and overdose from opioids than those in the general population.14 The patient and prescriber are often intertwined in challenging clinical and personal battles to manage their pain. Clinicians must optimize pharmacotherapy to improve patients’ quality of life. 
 
Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP, are clinical pharmacists in Pensacola, Florida. Matthew Bailey and Amanda Boyer are PharmD candidates at Auburn University in Alabama. Meagan Balding is a PharmD candidate at the University of Florida in Gainesville.

References 
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  12. Tutt B. Managing opioid use in cancer patients. MD Anderson website.mdanderson.org/publications/oncolog/managing-opioid-use-in-cancer-patients-.h12-1592202.html. Published March 2018. Accessed January 17, 2019.
  13. Chwistek M. Recent advances in understanding and managing cancer pain. F1000Res. 2017;6:945. doi: 10.12688/f1000research.10817.1.
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