According to the International Association of the Study of Pain, pain is defined as “an unpleasant, sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”

A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the United States in 2015. It is estimated that 48,960 men and women will be diagnosed with pancreatic cancer and 40,560 will die of the disease. Thirty percent of the patients with cancer have pain at the time of diagnosis, and 65% to 85% of patients with cancer have pain at advanced stages. Thirty-six percent have pain severe enough to impair their ability to function.

Vainio and Auvinen studied 1,840 patients with advanced cancer and found 24% with no pain, 24% with mild pain, 30% with moderate pain, and 21% with severe pain. Daut and Cleeland
found pain to be an early symptom of cancer in 48% to 50% of patients with cancer of breasts, ovary, prostate, colon, and rectum, and in 20% of patients with uterus and cervical cancer.

The components of cancer pain are sensory, affective, and psychological.

The sensory components could be nociceptive pain elicited by activation of sensory nerve endings by mechanical, chemical, radioactive, or thermal energy. It is often associated with ongoing tissue damage and may be of somatic or visceral origin. Somatic pain may be superficial, well localized, sharp, pricking, burning or deep diffused, dull, and aching. Visceral pain is usually diffuse, referred to body surface, and has a sickening quality to it.

Neuropathic pain is due to pathologic change in the discharge properties of the neurons because of invasion, compression, or damage caused by various cancer treatment modalities. It is typically described as burning, lancinating, painful numbness, or itching sensations. Phantom pain is a pain referred to the amputated part of the body. Psychological pain is usually due to fear, anxiety, depression, existential questions, anger, social and financial issues, social support, and the impact the pain has on the family and caregivers. Most cancer patients report more than one site of pain.

Sustained pain on its own can create complex, enduring, unpleasant emotional suffering by its ability to create awareness of the perceived threat to one’s life. It causes helplessness in the face of the inevitability of demise as well as exhaustion of hope. Patients with cancer usually identify pain as an indicator of disease progression. Suffering may be attributable to many factors besides physical complaints. Psychological factors include financial issues, lack of social support, loss of job or social position in society, loss of independence, effect on family and friends, social isolation, and fear of death.

The ultimate perception of pain depends on the nociceptive stimulus and psychological fear, anger, anxiety, or depression. Twenty-five percent of patients with cancer meet criteria for major depressive syndromes at some point in their illness, with an overall prevalence of 53% in hospitalized patients with cancer. Psychological factors may significantly exacerbate pain. The psychological suffering is associated with the disease and the imminence of death.

Symptoms usually include anxiety, restlessness and irritability, sleep disorders, obsessive thinking, slowness in motor responses, and hopelessness. Psychological suffering was most typically manifested in depression, which most of the patients suffer during the initial stages of the disease, when the disease metastasize, and when they are in a particularly poor condition. These factors affect overall pain behavior and suffering. General deterioration causes them to withdraw into their home or the hospital.

Pain in patients with cancer may be due to (1) presence and progression of the tumor itself, for example, bone involvement, viscus obstruction, and nerve compression; (2) indirect effect of the tumor, for example, metabolic imbalance, infection, and venous or lymphatic obstruction; (3) consequence of cancer treatment, such as chemotherapy, radiation therapy, or surgery; or (4) unrelated mechanisms such as migraine and myofascial pain.

Localized invasion of peripancreatic structures most commonly causes back pain, which stems from tumor invasion of the splanchnic plexus, common bile duct obstruction, retroperitoneum, or pancreatitis. This pain is described as severe, gnawing, epigastric, upper abdominal radiating to the middle of the back, worse on lying down and improved with upright position.

Grond et al. found in a prospective study of 2,266 patients with cancer that 30% had one pain syndrome, 39% had two pain syndromes, 31% had three pain syndromes, 85% by the cancer itself (bone, 35%; soft tissue, 45%; and visceral, 34%), and 17% by anticancer treatment.

Pain, in patients with cancer, may be classified on the basis of the following:

The pancreatic carcinoma usually presents with vague symptoms of anorexia, weight loss, abdominal discomfort, new-onset diabetes mellitus, or thrombophlebitis. The vague nature of symptoms may result in delay of diagnosis.

About 30% to 60% of patients present with pain, and 80% of the patients with advanced cancer complain of pain. Pain is diffuse epigastric radiating to the back that is increased on lying down and improved on sitting.

A stepwise approach is required for the assessment of pain. It includes history, physical examination, and data collection ending with clinical diagnosis. It helps the clinician achieve goals of providing pain relief. Assessment involves identifying features of pain, such as location, intensity, quality, timing, exacerbating/relieving factors, response to previous analgesics,
and disease-modifying treatments; effects of pain on daily activities and psychological state; associated symptoms; complete physical examination; and laboratory data and imaging.

Although abdominal pain may arise from different intraperitoneal structures, the retroperitoneal organs can cause similar pain symptoms. Location and radiation of the pain can give important clues to make the diagnosis. Retroperitoneal structures present with dull or sharp back pain that is increased on lying down and relieved on sitting hunched up. Abdominal tumors are frequently characterized by colicky pain associated with nausea that is worse after eating. Abdominal pain may be referred to distant areas like shoulder, neck, or back depending on the organ involved. Tumors of the small bowel or large bowel may present with symptoms of obstruction (e.g., abdominal distention, nausea, and bilious vomiting) or hematemesis or melena. Other common causes of abdominal pain include omental metastasis, volvulus of intestine, infectious peritonitis, radiation enteritis, and peritoneal carcinomatosis. Mesenteric ischemia presents with diffuse pain that is increased with meals and weight loss.

Nonmalignant causes of abdominal pain such as appendicitis, cholecystitis, and pancreatitis can occur in patients with cancer coincidentally and may complicate the diagnostic process. Opioid analgesics may not be used in these patients because they may exacerbate symptoms of colicky pain (due to spasm of sphincter of Oddi), nausea, vomiting, paralytic ileus, and constipation.

The World Health Organization advocated a stepladder approach to manage cancer pain exclusively with oral medications depending on the pain intensity and to some extent the pain mechanism (Fig. 49.1).

Step 1. Manage the pain by nonopioid medications with or without adjuvants.

Step 2. If pain is persisting or increasing, add weak opioids to nonopioid analgesics and adjuvants.

Step 3. Strong opioids are used with nonopioid analgesics and adjuvants until the patient achieves complete analgesia.

Step 4. A new fourth step has been recommended for treatment of crises or persistent chronic pain, and this includes transforaminal epidural steroid injections, lumbar percutaneous adhesiolysis and neurolysis, and other interventional procedures.

Noninvasive routes of drug delivery should be maintained as long as possible because of its simplicity, convenience, and cost.

Morphine is an opiate (naturally occurring in opium) by definition and is a µ-receptor opioid agonist. An ideal opioid agonist would have a high specificity for receptors producing desirable effects (analgesia and minimal or no affinity for other receptors that cause side effects). Opioids are unique in producing analgesia without loss of consciousness.

Morphine is the principal phenanthrene alkaloid present in opium and hence is termed an opiate. It is highly ionized and water-soluble. The most active molecule of morphine is the levorotatory isomer of stereochemical structure. The synthetic or semisynthetic compounds are called opioids and contain the phenanthrene nucleus of morphine. The terms opiates and opioids are often used interchangeably in clinical practice. Clinically, histamine release by morphine differentiates it from the synthetic opioids. This may cause urticaria, allergic reactions, and hemodynamic instability, particularly in volume-depleted patients.

The mixed-action opioids bind to µ-receptors, where they are partial agonists or competitive antagonists. Antagonistic properties of these drugs can attenuate the efficacy of subsequently administered opioid agonists and cause withdrawal symptoms in patients already receiving opioid agonists. The advantages of these drugs include low potential for respiratory depression and physical dependence. A dysphoric reaction is very common with mixed-action opioids. Their use is limited because of a ceiling effect whereby progressive escalation in doses does not increase analgesia as with opioid agonists.

The efficient oral and rectal absorption with prolonged duration of analgesic action of methadone makes it a highly effective and attractive oral drug for cancer pain management.

Methadone is a synthetic opioid with a unique agonist-antagonist action. Methadone is a µ-receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. Activation of NMDA receptors is involved in the development of hypersensitivity and central sensitization in neuropathic pain and tolerance to opioids. Because of the antagonistic effect at the NMDA receptor site, methadone is very effective in neuropathic pain secondary to cancer-related pathology and therapeutic interventions. The same antagonistic action of methadone minimizes the development of tolerance to opioids.