INTRODUCTION:

Cancer and Tumors conditions do not respond to body mechanisms that limit cell growth leading to abnormal cellular growth. Cancer cells, unlike normal cells, lack contact inhibition; cancer cells grow unanimously as they touch each other. Loss of contact inhibition accounts for two other characteristics of cancer cells: invasiveness of surrounding tissues, and metastasis, or spreading via the lymph system or blood to other tissues and organs. Cancer tissue, growing without limits, competes with normal tissue for nutrients, eventually killing normal cells by nutritional deprivation [1-2]. Cancer is the second leading cause of death nowadays.

Pain in cancer may arise due to various reasons like tumor compressing or infiltrating to nearby body parts, from treatments and diagnostic procedures and also due hormonal imbalance or immune response. Most chronic (long-lasting) pain is caused by the illness and most acute (short-term) pain is caused by treatment or diagnostic procedures. However, radiotherapy and chemotherapy may also contribute to pain conditions which may be prolonged even after the end of the treatment.

The presence of pain depends mainly on the location of the cancer and the stage of the disease [3]. At any given time, about half of all patients with malignant cancer are experiencing pain, and two thirds of those with advanced cancer experience pain of such intensity that it adversely affects their sleep, mood, social relations and daily activities. Worldwide, nearly 80 percent of people with cancer receive little or no pain medication.

Guidelines for the use of drugs in the management of cancer pain have been published by the World Health Organization (WHO)[4], EAPC guidelines [5] and others[6]. Healthcare professionals have an ethical obligation to ensure that, whenever possible, the patient or patient's guardian is well-informed about the risks and benefits associated with their pain management options. Adequate pain management may sometimes slightly shorten a dying patient's life.

Pain Associated With Cancer:

Pain from cancer of the organs, such as the stomach or liver (visceral pain) is often called as referred pain, as they diffuse and are difficult to locate [7].

Some diagnostic procedures, such as lumbar puncture, venipuncture, paracentesis, andthoracentesis can be painful [8].

Treatment-related pain [7-9]:

1. Immunotherapy which may produce joint or muscle pain;

2. Radiotherapy, which can cause skin reactions, enteritis, fibrosis, myelopathy, bone necrosis, neuropathy or plexopathy;

3. Chemotherapy, often associated with chemotherapy induced peripheral neuropathy, mucositis, joint pain, muscle pain, and abdominal pain due to diarrhea or constipation;

4. Hormone therapy, which sometimes causes pain flares;

5. Targeted therapies, such as trastuzumab and rituximab, which can cause muscle, joint or chest pain;

6. Angiogenesis inhibitors like bevacizumab, known to sometimes cause bone pain;

7. Surgery, which may produce post-operative pain, post-amputation pain or pelvic floor myalgia.

Post-operative pain:

Relieving pain resulting from surgery helps people recuperate more quickly and heal more effectively [10].

Pain that is not well controlled can develop into chronic pain. So it is important to take prescribed analgesic to control this or else it becomes harder to control in the future. The amount of pain in cancer depends on:

1. The type of cancer, one has the location of cancer / tumor, the stage of cancer development and whether the cancer or treatment has damaged any nerves.

2. Other factors such as fear, anxiety, depression and a lack of sleep can also affect how you feel pain.

The symptoms of cancer pain vary from person to person. The amount of pain may depend on the type of cancer, the stage or extent of the disease, and the person's pain threshold (tolerance for pain). Pain can range from mild and occasional to severe and constant.

Mechanism of Cancer Pain:

Many researchers have unraveled about cancer-induced neuropathologic processes that occur in the region of tumor growth and in the dorsal horn of the spinal cord [10]. Within the cancer microenvironment, cancer and immune cells produce and secrete mediators that activate and sensitize primary afferent nociceptors [11, 12]. Pursuant to these peripheral changes, nociceptive secondary neurons in spinal cord exhibit increased spontaneous activity and enhanced responsiveness to three modes of noxious stimulation: heat, cold, and mechanical stimuli.

Endothelin (ET-1) play dual role in Cancer-Induced Nociception [13]:

ET-1 is a potent vasoactive peptide that produces nociceptive behavior and drives cancer pain. There are two endothelin receptor subtypes that differentially affect opioid release from carcinomas, on activation by ET-1.

ET-1 binds to two G protein–coupled receptors, the endothelin-A receptor (ETAR) and the endothelin-B receptor (ETBR). ETARs are distributed on peripheral sensory neurons; ETBRs are expressed on nonmyelinating Schwann cells of the sciatic nerve and dorsal root ganglion satellite cells as well as on keratinocytes, which are known to secrete opioids. The ETAR primarily mediates vaso-constriction, mitogenesis, antiapoptosis, and acute pain whereas ETBR mediates inflammatory pain and vasodilatation.

ETBR and Opioid Release [14, 15]:

Upregulation of ETB receptors in cancer cells had been observed in melanoma, breast cancer, and ovarian cancer whereas ETBR down-regulation was observed in prostate, bladder, and colorectal cancer. ETBR antagonism hindered tumor proliferation. In non-cancerous pain, ETBR mediates both nociceptive and antinociceptive effects of ET-1. ETBR activation was shown to produce an antinociceptive effect in the context of high ET-1 concentration or in the local setting of inflammation. Electrophysiologic experiments also support the anti-nociceptive effect of ETBR agonism. ET-1 that is applied to cutaneous nerve endings produces action potentials that can be strongly suppressed with ETBR agonists and ETAR antagonists.

Most notable is the recent finding that links production of β-endorphin with ETBR activation. mRNA in the SCC cancer pain model and showed that ET-1 expression was nearly doubled, whereas ETBR expression was significantly down-regulated in the human oral SCC cell line (compared to normal oral keratinocytes, the non-malignant counterpart to oral SCC). In the mouse model, the intratumor administration of an ETBR agonist attenuated cancer pain by approximately 50% up to 3 hours post-injection, whereas injection of an ETBR antagonist had no effect. Intriguingly, local naloxone methiodide or injection of selective μ-opioid receptor antagonist (CTOP) reversed ETBR agonist-induced antinociception in cancer animals.

ETBR agonism attenuates carcinoma pain by modulating β-endorphins released from the carcinoma to act on peripheral opioid receptors. Oral squamous cell carcinoma consists of malignant keratinocytes that bear ETB receptors and secrete opioids to modulate the activity of the surrounding primary afferent nociceptors in skin. In addition, ET-1 activation of ETBRs on keratinocytes leads to analgesia that is reversed with naloxone, implicating the keratinocytes as a source of opioid released upon ETBR activation.

Chronic Pain:

Chronic pain is a condition where pain is severe and prolongs for a long time. There are basically two chronic pain types:

Neuropathic pain [16, 17]:

Neuropathic Pain, also known as nerve pain is a complex, chronic pain state which is accomplished nerves are damaged or injured in CNS. Which impacts change in nerve function both at the site of injury and areas around the injury [18]. Such injuries can give rise to paresthesias, such as numbness, tingling, or electrical sensations. Neuropathic pain can also generate unusual symptoms, such as anesthesia dolorosa, in which the area producing the pain is numb to the touch.

Nociceptive pain [16, 17, 19]:

Nociceptive pain stimulus is transmitted by peripheral nerves from specialized pain receptors, called nociceptors, whose function is to report any injury, which in cancer patients is usually secondary to invasion of tumor into bone, joints, or connective tissue. Nociceptive pain can be somatic, visceral associated with invasive procedures, ie, lumbar puncture, biopsy, surgical intervention and also due mechanical or metabolic injury to the nervous system itself. In patients with advanced cancer this can be a result of tumor infiltration of nerves or nerve roots, as well as iatrogenic in nature as a result of exposure to chemotherapeutic agents (ie, vinca alkaloids) or radiation therapy.

Nociceptive, or somatic, pain is the common discomfort we have all experienced as a result of injury -- a paper cut, a broken bone, or appendicitis, among other things. Somatic pain makes sense to us; we can understand the patient's pain.

Chronic pain may be continuous with occasional sharp rises in intensity (flares or breakthrough pain), or intermittent: periods of painlessness interspersed with periods of pain.

Break Through Cancer Pain [20]:

Breakthrough pain is a distinct pain state that is common in patients with cancer pain and which is associated with significant morbidity in this group of patients. Breakthrough cancer pain (BTCP) is almost unrecognized and inadequately treated and often unresolved in many cancer patients. BTCP is categorized as spontaneous pain and incident pain:

· Spontaneous pain (‘idiopathic pain’) – these episodes are not related to an identifiable precipitant and so, are unpredictable in nature.

· Incident pain (‘precipitated pain’) – these episodes are related to an identifiable precipitant, and can be generally predictable in nature. Incident pain is usually sub-classified into one of three categories: (

· Volitional incident pain – brought on by a voluntary act (e.g., walking)

· Non-volitional incident pain – brought on by an involuntary act (e.g., coughing)

· Procedural pain – related to a therapeutic intervention (e.g., wound dressing).

There is a at most need of knowledge of location (usually the same as background pain), severity (usually more severe than the background pain – e.g., considered ‘severe’ or ‘excruciating’), temporal characteristics (number of episodes per day, onset, duration) precipitating factors (incident or spontaneous), predictability (predictable, unpredictable), pathophysiology (nociceptive, neuropathic, or mixed), aetiology (cancer, cancer treatment, or unrelated to cancer), palliative factors (e.g., relieved by the use of analgesia or by restricting movement) [21].

BTCP is managed by focusing on reducing the intensity, severity, and effect of each pain episodes. The management of BTCP should be individualized to each patient, with the optimal approaches depending on a variety of pain- and patient-related factors. It needs a comprehensive, multidisciplinary approach and a combination of management strategies, which may include pharmacological and non-pharmacological treatment modalities [21].

It is important to keep in mind that cancer patients will generally experience a combination of pain types, and the treatment of the disease, i.e, surgery, radiation, chemotherapy, may be an important source of the painful stimuli along with progression of the disease itself.

Treatment of Cancer Pain by using Opioids:

Opioids are widely used for treatment of pain in patients with cancer because of their safety, multipleroutes of administration, ease of titration, reliability, and effectiveness for all types of pain (ie, somatic, visceral, neuropathic)[22]. Opioids are also potentially abusable drugs. There are,WHO guidelines [4], EAPC guidelines [5] and few of the guidelines [6] recommended to physicians for cancer pain treatment using opioids.

Step 1 on the WHO pain relief ladder treats mild pain. Patients in this category receive nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs, or an adjuvant analgesic, if necessary. Step 2 treats patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but who are still experiencing poor analgesia. Step 2 agents include tramadol and acetaminophen products containing hydrocodone, oxycodone, and codeine. Step 3 treats moderate to severe pain with strong analgesics. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone, oxymorphone, and oxycodone. An open-label randomized trial of low-dose morphine versus weak opioids to treat moderate cancer pain suggests that it is acceptable to bypass weak opioids and go directly to strong opioids (step 3 agents) for patients with moderate cancer pain, as patients randomly assigned to the low-dose morphine arm had more frequent and greater reduction in pain intensity with similarly good tolerability and earlier effect.

Figure 1: Three-step ‘ladder’ for pain relief by WHO [23]

Opioids are used to treat acute pain related to surgery and other medical procedures, as well as for persistent (chronic) and breakthrough pain that is moderate to severe. Persistent pain is usually treated with long-acting opioids. If there are episodes of breakthrough pain, a second short-acting opioid may be prescribed as well [24].

The opioid of first choice for moderate to severe cancer pain:

· Morphine is the standard ‘step 3’ opioid analgesic against which others are measured and is the most widely available in a variety of oral formulations. Morphine appears to have no clinically relevant ceiling effect to analgesia: doses of oral morphine may vary 1000- fold or more to achieve the same end point of pain relief.

· The opioid of first choice for moderate to severe cancer pain is morphine.

1. Oral transmucosal fentanyl citrate (OTFC) is an effective treatment for ‘breakthrough pain.

2. Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria the application of the WHO and the EAPC guidelines (using morphine as the preferred step 3 opioid) permit effective control of chronic cancer pain in the majority of patients.

· Over-the-counter and prescription-strength pain relievers, such as aspirin, acetaminophen (Tylenol, others) and ibuprofen

· Weak opioid (derived from opium) medications, such as codeine

· Strong opioid medications, such as morphine oxycodone (Oxycontin, Roxicodone, others), hydromorphone (Dilaudid, Exalgo), fentanyl (Actiq, Fentora, others), methadone (Dolophine, Methadose) or oxymorphone (Opana) [22-25].

These drugs can often be taken orally, so they're easy to use. Medications may come in tablet form, or they may be made to dissolve quickly in your mouth. However, if you're unable to take medications orally, they may also be taken intravenously, rectally or through the skin using a patch.

Opioid Analgesics should not be taken "on demand" but "by the clock" (every 3–6 hours), with each dose delivered before the preceding dose has worn off, in doses sufficiently high to ensure continuous pain relief. People taking slow-release morphine should also be provided with immediate-release ("rescue") morphine to use as necessary, for pain spikes (breakthrough pain) that are not suppressed by the regular medication [26-27].

Tapentadol:

Tapentadol is a centrally-acting synthetic opioid analgesic, having potencybetween morphine and tramadol [28] The U.S. Drug Enforcement Agency has placed Tapentadol into Schedule II of the Controlled Substances Act [29]. The approval of the drug was based on data from clinical studies proving tapentadolfor significant relief of moderate to severe acute pain in adults 18 years of age or older [30].

It has a unique dual mode of action as an agonist at the µ-opioid receptor and as a norepinephrine reuptake inhibitor [28]. As a mu-opioid agonist, it binds to and activates mu-opioid receptors in the central nervous system. It modifies sensory and affective aspects of pain, inhibits the transmission of pain at the spinal cord and affects activity at parts of the brain that control pain perception. Tapentadol also exerts its analgesic effect by increasing the level of norepinephrine in the brain by inhibiting its re-absorption into nerve cells because of its norepinephrine reuptake inhibitory property at the central nervous system sites [28, 30].

Postoperative pain after bunionectomy: It can be compared with morphine and ibuprofen for relief of pain after foot surgery [31], tapentadol produced equally good pain relief with less nausea and dizziness. Multiple doses of Tapentadol IR also have produced comparable relief from acute pain with improved gastrointestinal tolerability, against oxycodone IR. [31] Pain due to metastatic bone tumours has also shown good results [32].

The limitation to the use of tapentadol and other opioids are because of their side effects like respiratory depression, CNS depression, misuse and abuse, withdrawal, hepatic and renal impairment, and other minor ones. When compared to chronic NSAID therapy, the Tapentadol shows better G.I tolerability (specifically in the incidence of nausea, vomiting, and constipation) along with no risk of gastrointestinal ulceration and bleeding. Even Tapentadol is better in regard to concerns of tolerance and dependence when compared to non-opioid and other opioidal drugs such as morphine and codeine for the treatment of acute or chronic pain [33-34].

Long term treatment with sustained release Tapentadol once daily is generally safe in patients with cancer related pain. It has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep and improved compliance [34]. Marketed extended release dosage forms: Nucynta, Palaxia ,Palaxia depot , Palaxia Retard, Trapil.

Some advantages of Tapentadol as extended release tablet over conventional dosage form include increasing half-life, more gastrointestinal absorption, reduced dosing frequency, maintain therapeutic concentrations, minimize accumulation by chronic dosing, less usage of drug and provide special effects, least fluctuation in plasma drug concentration, reduce local and systemic side effects there by improve treatment efficacy, etc, [35].

Reasons for In-Adequate Treatment for Cancer Pain [36-37]:

1. Reluctance of doctors to ask about pain or offer treatments. Some doctors and other health care professionals may not specifically ask about pain, which should be a normal part of every visit with your doctor.

2. Reluctance of patients to speak up about pain

3. Fear of addiction

4. Fear of side effects.

Additional care required:

1. Taking medications regularly, according to the advice of the doctor.

2. Knowing patient’s medication – how it works, lasts in the body, its side effects are and any other particularities.

3. Up-to-date record of patient’s current medication and dose.

4. Taking enough medication before bed to ensure an uninterrupted sleep.

5. If necessary, patient may need to set alarm during the night, so that he doesn’t miss a dose.

6. Medications to be reviewed regularly by the doctor.

7. Writing down the date and time of the pain experienced and for how long it lasted.

CONCLUSION:

Pain related to cancer is as well important as the cancer itself. A cancer is associated with different types of pain staring from Visceral, Referred pain, Somatic pain, Nociceptic pain, Neuropathic pain, Breakthrough pain, etc., which becomes chronic and severe with the onset of cancer to the treatment and even after surgeries. To make the treatment of cancer effective, the treatment of pain should also be given an equal importance.

REFERENCES:

1. Filip Janku, David J. McConkey, David S. Hong and Razelle Kurzrock. Autophagy as a target for anticancer therapy. Nature Reviews Clinical Oncology 2011; 8: 528-39.

2. Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 24.1, Tumor Cells and the Onset of Cancer. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21590/.

3. Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK164700/.

4. S. Mercadante and F. Fulfaro. World Health Organization guidelines for cancer pain: a reappraisal. Annals of Oncology 16 (Supplement 4): iv132 –iv135, 2005.

5. Caraceni A, Hanks GW, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012; 13: 58-68.

6. National Comprehensive Cancer Network. Cancer pain treatment guidelines for patients (version II) [online] 2005. Accessed 4 April 2006. URL: http://www.nccn.org/patients/patient_gls.asp.

7. Shafaq Sikandar and Anthony H Dickenson. Visceral Pain – the Ins and Outs, the Ups and Downs. Curr Opin Support Palliat Care. 2012 March; 6(1): 17–26.

8. Russell K Portenoy, Pauline Lesage. Management of cancer pain. The Lancet 1999; Volume 353, No. 9165, p1695-1700.

9. Hrachya Nersesyan and Konstantin V Slavin. Current approach to cancer pain management: Availability and implications of different treatment options. Ther Clin Risk Manag. 2007 Jun; 3(3): 381–400.

10. Matthew RD Brown, Juan D Ramirez and Paul Farquhar-Smith. Pain in cancer survivors. Br J Pain. 2014 Nov; 8(4): 139–153.

11. Brian L. Schmidt, Darryl T. Hamamoto, Donald A. Simone and George L. Wilcox. Mechanism of Cancer Pain. MolInterv. 2010 Jun; 10(3): 164–178.

12. B. L. Schmidt, “The neurobiology of cancer pain,” Neuroscientist 2014; 20 (5): pp. 546–562.

13. Alla Khodorova, Jean-Pierre Montmayeur and Gary Strichartz. Endothelin Receptors and Pain. J Pain. 2009 Jan; 10(1): 4–28.

14. Terika P Smith, Tami Haymond, Sherika N Smith and Sarah M Sweitzer. Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain. J Pain Res. 2014; 7: 531–545.

15. Khodorova A, Navarro B, Jouaville LS, et al. Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med. 2003; 9(8):1055–1061.

16. Diana J. Wilkie, Hsiu-Ying Huang, Nicole Reilly and Kevin C. Cain. Nociceptive and Neuropathic Pain in Patients with Lung Cancer: A Comparison of Pain Quality Descriptors. J Pain Symptom Manage 2001: 22:899–910.

17. Price D, Dubner R. Mechanisms of first and second pain in the peripheral and central nervous systems. J Invest Dermatol. 1977; 69(1):167–171. doi: 10.1111/1523-1747.ep12497942.

18. Azhary H, Farooq MU, Bhanushali M, Majid A, Kassab MY. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician (2010) Apr 1; 81 (7): 887-92.

19. Adrienne E. Dubin and Ardem Patapoutian. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010 Nov 1; 120(11): 3760–3772.

20. Seema Mishra, Sushma Bhatnagar, Prakash Chaudhary, and Shiv Pratap Singh Rana. Breakthrough Cancer Pain: Review of Prevalence, Characteristics and Management. Indian J Palliat Care. 2009 Jan-Jun; 15(1): 14–18.

21. Breakthrough cancer pain guidelines 2013. European Oncology Nursing Society guidelines. https://www.cancernurse.eu/ documents/EONSBreakthroughCancerPainGuidelines.pdf.

22. Columba Quigley. The role of opioids in cancer pain. BMJ. 2005 Oct 8; 331(7520): 825–829.

23. Cancer pain relief with a guide of opioid availability. Second edition. WHO Geneva 1996.

24. Ørnulf Paulsen, Stein Kaasa and Ola Dale. Do Corticosteroids Provide Analgesic Effects in Cancer Patients? A Systematic Literature Review. J Pain Symptom Manage 2013; 46: 96-105.

25. Plante GE and VanItallie TB. Opioids for cancer pain: the challenge of optimizing treatment. Metabolism. 2010 Oct; 59 Suppl 1:S47-52.

26. Giovambattista Zeppetella. Opioids for the management of breakthrough cancer pain in adults: A systematic review undertaken as part of an EPCRC opioid guidelines project. Palliative Medicine. 2010; 25(5): 516–524.

27. Jane C. Ballantyne. Chronic Pain Following Treatment for Cancer: The Role of Opioids. The Oncologist December 2003vol. 8 no. 6 567-575.

28. Dewan Roshan Singh, Kusha Nag, Akshaya N. Shetti, and N. Krishnaveni. Tapentadol hydrochloride: A novel analgesic. Saudi J Anaesth. 2013 Jul-Sep; 7(3): 322–326.

29. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement of tapentadol into schedule II. Final rule. Fed Regist. 2009 May 21; 74(97):23790-3.

30. Nalini Vadivelu, Alexander Timchenko, Yili Huang and Raymond Sinatra. Tapentadol extended-release for treatment of chronic pain: a review. J Pain Res. 2011; 4: 211–218.

31. Stegmann JU, Weber H, Steup A, et al. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunionectomy) surgery. Curr Med Res Opin. 2008; 24(11):3185–3196.

32. Falk S, Patel R, Heegaard A, Mercadante S, Dickenson AH. Spinal neuronal correlates of tapentadol analgesia in cancer pain: a back-translational approach. Eur J Pain. 2015 Feb; 19(2):152-8.

33. Adam M. Kaye, Alan D. Kaye and Elise C. Lofton. Basic Concepts in Opioid Prescribing and Current Concepts of Opioid-Mediated Effects on Driving. Ochsner J. 2013 winter; 13(4): 525–532.

34. Frampton JE. Tapentadol immediate release: a review of its use in the treatment of moderate to severe acute pain. Drugs. 2010 Sep 10; 70(13):1719–1743.

35. Michael J Brennan. Update on prescription extended-release opioids and appropriate patient selection. J Multidiscip Healthc. 2013; 6: 265–280.

36. Victoria Campbell. The challenges of cancer pain assessment and management. Ulster Med J. 2011 May; 80(2): 104–106.

37. Edward Chow, et al,. Inadequate pain management in cancer patients attending an outpatient palliative radiotherapy clinic. Support Care Cancer (2016) 24:887–892.

Received on 28.06.2017 Accepted on 22.08.2017

Asian J. Res. Pharm. Sci. 2017; 7(4):183-188.

DOI: 10.5958/2231-5659.2017.00028.5

ABSTRACT: