David S. Klein, M.D.

Cancer Pain

Pain in the Patient Who Suffers from Cancer

Pain is a common complaint among patients undergoing treatment for many types of cancer. While not all people with cancer will experience pain, 30% to 50% of people with cancer, experience pain while undergoing treatment. Pain can be caused by the disease itself or by the treatments intended to treat the cancer.

Incidence and Prevalence

Approximately 90% of patients with advanced cancer experience severe pain. Pain can be expected to plague 30% to 50% of all patients irrespective of staging. Inadequate or incomplete pain treatment will be experienced by as many as 50% of all cancer patients. Pain is not a symptom of the early stages of cancer, but complaints of pain increase as the neoplasm develops over time.

The nature of cancer is that it often involves multiple parts of the body. The result is that pain is likely to manifest in different parts of the body. Over 80% of patients experience pain two distinct locations, and more than 30% experience pain in three or more locations.

Etiology

Pain in the cancer patient can result from cancer growth, cancer treatment, and pain can result from sources unrelated to the cancer itself.  Pain can also occur completely independent of cancer or its treatment. To the patient with cancer, every headache, backache, twinge or spasm is suspect for being a new site of metastasis. Arthritis and  other ailments are common. It is very easy, indeed, to attribute every ache, pain, and misery to the neoplastic process, and thereby forget that ordinary and easily treatable causes of pain are overlooked.

Pain depends on many factors such as the type of cancer, the stage of the disease, and the patient’s tolerance. Cancer pain can be directly related to tissue damage from tumors that destroy or press on tissues, bones, and nerves or block hollow structures such as parts of the digestive system, blood vessels, and lymph vessels.

Cancer pain can result from the following:

• Bone fracture from metastasis
• Inflammation Tumor exerting pressure on a nerve Blocked blood vessels causing poor circulationBlocked bowel, bladder Infection Alteration in nerve excitabilityCerebral pressure

• Side effects from cancer treatments (e.g., chemotherapy, radiation)

With regards to pain resulting from cancer growth, the most common cancer-induced pain results from tumor metastasis to bone. The incidence of pain in bone metastasis is between 60–80% of patients.

The second most common cause of cancer-related pain is caused by tumors infiltrating nerve and organ. Tumors near neural structures often cause the most severe types of pain. Injury to or compression of nerves or other components of the nervous system, results in pain that is termed neuropathic. Often due to damage to the vasonervorum and nervi nervorum, neuropathic pain is most commonly ‘burning’ in nature.

The third most common type of pain associated with cancer occurs as a result of cancer treatment, that is, chemotherapy, radiation, or surgery.

Pathophysiology

As defined by the International Association for 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." Pain is an emotion, and it is thereby very difficult to measure, and it is certainly difficult to define.  What is easy to recognize is that pain is a sensation/emotion that is experienced by all, at one time or another in life, and the reaction to pain is as individual as fingerprints and facial features.

Pain receptors are widely distributed throughout the body.  Present in the skin, viscera, bone and mucous membranes, pain receptors are triggered by mechanical, chemical, or thermal stimuli.  Most of the noxious pain signals are transmitted through somatic nerves to the spinal cord and subsequently to the brain.

Pain may also be caused by inflammatory response to ongoing nerve-tissue damage. This nociceptive pain is further categorized by site of origin.  Visceral pain results from injury to an internal organs- often hard to localize, the pain is described as throbbing, aching, gnawing or sharp. Somatic pain commonly  involves bone and joint. It is more easily localized, and is described as throbbing, aching, or sharp.Many pain signals are transmitted to the brain by pathways outside of the well-defined axial pathways, and travel via the autonomic nervous system. It is these autonomic afferent signals that are the most difficult to interpret, and it is these signals that cause most of the pain of neoplastic origin.

Acute pain will cause familiar physiological signs to appear, such as grimace, tachycardia, diaphoresis, and tachypnea. Eventually, these physiological signs attenuate, and eventually disappear, entirely. This transition is observed to take several months to complete. The disappearance of these ‘objective’ signs of pain do not imply that the pain has abated, or that the disease process is improving.

Treatment induced pain syndromes

Chemotherapy is well known to cause serious side effects, including those that result in pain.  Depending upon the nature of cellular damage, the types of chemotherapy induced pain vary with the secondarily damaged tissues. Treatment is very different for each type of side-effect, and some of the most effective treatment is easy, economical and available.Damage to the gastro-intestinal mucosa is a very common side effect, and it causes the most noticeable mouth sores (mucositis), esophageal erosion, gastrointestinal sloughing, as well as peri-anal inflammation. Damage to the lining of the respiratory tract results in cough, pleuritic pain and dyspnea.Peripheral neuropathy commonly results from a variety of chemotherapy agents.  Affecting the longest nerves first, numbness & tingling in the hands and feet can occur earlier than symptoms affecting the torso. Sensory nerves are generally more susceptible to chemotherapy-induced damage than are the larger motor-fibers.  Numbness and sometimes painful sensations in the feet, legs, fingers, hands and arms generally precedes weakness.  Autonomic fibers may be the earliest nerves injured, resulting in constipation, blurred vision, diarrhea, nausea, vomiting and abdominal cramps. Eyes and ears are affected more commonly by anti-biotic chemotherapy agents than from other types of agents.

Radiation therapy can result in both peripheral neuropathic processes as well as central/axial myelopathic pain syndromes.  The damage is usually delayed in onset, and insidious in development.

Surgical treatments will, in some instances produce pain after they are  completed. Your physician and nurse will provide medications and techniques to help you manage surgery-related pain.  Procedures related to cancer pain, such as biopsy, venipuncture, lumbar puncture, thoracentesis, and so forth cause significant anxiety to the patient.

“Severity of pain is not necessarily proportional to the severity of illness.”

Pharmacologic & Anesthetic Approach to the Treatment of Pain. 

Imperperative to the adequacy of treatment of all medical conditions, accurate diagnosis is essential to the success of pain treatment. Bone pain is caused by chemical mechanisms that involve a number of directions, including the familiar cyclo-oxygenase pathways, leukotriene and histamine pathways, neutrophil chemotactic factor, tumor necrotic factor, to name but a very few. The first step involves the selection of agent(s) reflects the nature of the tissue-destructive pathway(s), and only then do we move on to therapeutic steps that involve nerve pathways, higher level integration & cognition.

Cancer pain may be defined as ‘chronic. Severity can range from mild to severe.Breakthrough pain is defined as a ‘temporary flare’ in pain intensity, due to an acute change in disease state, or due to decreases in blood/tissue level of the analgesic. Breakthrough pain can be anticipated prior to development of the most effective medication ‘cocktail.’ Individuals respond differently, and the process of medication selection involves some degree of trial and error. Breakthrough pain will occur even when the patient takes the ultimately effective and proper pain medication protocol. Allowances must be made to permit the patient some latitude in medication utilization, for these times.

The most important analgesics in the treatment of cancer-related pain are not opiates. The ‘adjuvant’ analgesic medications provide the greatest pain relief for the greatest number of patients. Opiates should be used as adjuncts to the non-opiate agents, for greatest pain relief.Neuropathic and nociceptive pain, respond very differently to pain medications. For neuropathic pain, the anti-convulsants, calcium-channel modulators, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, anti-depressants, and are more effective than opiates.

Pain-relieving medicines can be prescribed to meet various kinds of cancer-related pain. They can also be administered by different routes, depending on a patient's individual needs and preferences. Analgesics are given orally, rectally, transmucosally, intravenously, intrathecally, epidurally, subcutaneously, or transdermally. They may also be delivered by means of patient-controlled analgesia (PCA), in which patients help control the amount of pain medication by pressing a button on a computerized pump.

Mild to Moderate Pain

Non-opiate drugs such as acetaminophen (Tylenol) and non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen provide relief for many types of mild to moderate pain, including muscle pain, bone pain, and the pain of some incisions. Non-opiate analgesics work much better than opiates for muscular and visceral pain. Non-opiate analgesics, GABA agonists and muscle relaxants should be given first. These may be prescribed in combination with opiate and other therapies for greater pain relief.

Opiates (hydromorphone, methadone, morphine, fentanyl, codeine, oxycodone) are highly effective medicines for relieving cancer pain. Opiates are combined with non-opiate drugs (acetaminophen, aspirin, NSAIDs) for treatment of moderate pain. Addiction & habituation are not at issue in this patient population. Selection of analgesic should reflect duration of action, onset of action, liver and kidney toxicity.

Moderate to Severe Pain

• Droperidol is perhaps the most potent medication for the treatment of nausea. Usually given intra-venously, droperidol is 1000 times more potent than thorazine for the treatment of nausea.
  • Droperidol can be given sublingually, however. Sublingual titurates or troches can be made to deliver 0.1 mg doses, given 2-3 times daily. Duration of action is around 12 hours.
• Anti-depressants of the SSRI group.
  • Given early in treatment, nausea can be prevented, and patients can actually gain weight while on chemotherapy.
• Cathartics are given if bowel becomes obstructed.  Mineral oil floated on orange juice works well, in most circumstances.
• If nausea presents as motion sickness, anti-histaminics may provide some relief. These will cause confusion in the elderly, however
• If the pain medication is the cause of the nausea, increasing the opiate dose may relieve the nausea.
  • Some patients believe that they are allergic to opiates if they cause nausea. Nausea and vomiting are not allergic responses. Rash, on the other hand, may be an allergic reaction.

Patients may receive opiates for many years without developing addiction. This is not to say, however, that abrupt discontinuation is either safe of a wise action. As analgesic requirements decrease, or when pain subsides, any physical/physiologic dependence can be managed without development of withdrawal symptoms. Gradual tapering of opiate dosage, combined with administration of moderate doses of alpha & beta adrenergic blockers will attenuate or eliminate withdrawal symptoms.

Breakthrough Pain

Analgesics with rapid action are used to treat break-through pain.  Acting as a "rescue medication," morphine, hydromorphone, oxycodone and hydrocodone should be made available to the patient for  pain "breaks through." This is an expected aspect of pain control in this population.

Adjuvant Analgesics

Many medications will provide pain relief and help manage cancer-related pain. Most of these medications have primary uses that might appear to be far-removed from pain control.  The commonly used expectorant, guaifenesin is a remarkable muscle relaxant, and the anti-tussive, dextromethorphan is used as an NMDA modulator that enhances opiate effect.>

The anti-convulsants are some of the most effective medications in the treatment of neuropathic pain.  When used in combinations reflecting both GABA_(A) and GABA_(B)  activity, these medications provide rather rapid and remarkably effective analgesic effect. For refractory neuropathic pain, the addition of calcium channel modulators, such as Lyrica® (pregabalin) and Neurontin® (gabapentin)  may provide remarkable analgesia.

Steroids, non-steroidal agents, anti-histamines, local anesthetics and anti-depressants are used with excellent results. These agents have been found to help relieve specific types of neuropathic pain, often described by the patient as  "tingling" and "burning" sensations, and pain caused by inflammation (swelling).

Topical ant-inflammatories, topical anti-convulsants (e.g. mixtures of flurbiprofen & gabapentin) provide rapid and effective relief of pain due to nerve damage.  Most effective for the treatment of conditions that result from superficial nerve damage, side-effects are minimal,  and analgesic relief can be expected within minutes.

Nerve Blocks

For acute (and postoperative) pain, enthesopathic and skeletal pain, nerve block using local anesthetic and anti-inflammatory combinations will provide temporary relief. Th injection of local anesthetic into or around nerve, bursa, tendon and periosteum provides immediate relief. The anesthetic interrupts transmission of pain signals to the spinala cord an brain, thereby providing relief for to several hours to months. By using dilute phenol, Sarapin or dextrose, a neurolytic block (neurolysis), is performed, and longer durations of pain relief can be achieved.  This is not to be confused by spinal/epidural neurolysis, whereby absolute alcohol or higher concentration phenol is injected around the spinal nerve roots, ganglia or directly into the spinal fluid.  Considerably more dangerous, the pain pathway itself is destroyed.  If safely administered, this may have long-lasting or permanent effect.

Nerve blocks work best for pain that occurs over a discrete location. For pain that is more widespread or regional, it is possible to modulate pain signals using techniques that place medications close to the spinal cord, in proximity to chemoreceptors that modulate pain signal integration.  Commonly used devices include epidural or intrathecal pumps.   The catheter portion of the device resides in the epidural or intrathecal areas of the spine, and the mechanical  pump that feeds the medication is  either carried in a pouch or placed under the skin.  Medication delivery can be continuously or used by ‘program.’  Pain relief can be achieved to much broader areas, and many of the opiate-side effects are minimized. Through delivery of medicine directly to CNS, somewhat less medication may be needed.

1. Pain medicines are taken on a regular schedule that is, by the clock, rather than p.r.n. or ‘as needed.’  This single step is the most important in the prevention of  persistent or chronic pain. The longer-acting medications work best in providing the foundation of therapeutic selection.
2. For breakthrough pain, short-acting medicines are the preferred choices.
3. Ensure that only one doctor prescribes pain medicines as well as adjunctive medications. These patients are among the most complicated, and it serves little advantage to have more than one physician ‘turning the dials.’
4. Remember that pain medicines affect different people in differently.
5. If a medication or approach is ineffective, it makes little sense to push the doses higher and higher.  The patient response is revealing an important physiological bit of information.  That is, another different pathway or mechanism is responsible for the symptoms, and it is time to re-assess the situation.

Medication Delivery Options

There are many choices in route of medication administration:

1. Orally
2. Skin patch
3. Rectal suppositories
4. Sublingually
5. Subcutaneously
6. Intramuscularly
7. Trans-nasally
8. Epidurally
9. Intrathecally

Choice of medication may dictate the route of administration.  It should be noted, however, that side-effects such as nausea, vomiting, and itching occur with opiates regardless of route of administration.  These side-effects result from stimulation of the chemotactic trigger zone (CTZ), Area Postrema near the 4^th ventricle. Nausea and vomiting are most common with the least potent of opiates, and amelioration can be expected by increasing the opiate dose or selecting a more potent agent.

Common side effects of opiates include drowsiness, constipation, nausea, and vomiting, dizziness, dysphoria, nightmares, confusion, hallucinations,  moderate decrease in rate and depth of breathing, difficulty in urinating, or itching.

Constipation

Opiates will constipation to some degree in most people. Bowel motility decreases allowing more time for the colon to absorb water from the stool. The stool  hardens. Prevention of constipation should be considered on each and every patient that is treated for pain.

Stool softeners.  Commonly used detergent agents.Unfortunately, these add nothing to nutrition.

• By substituting fish oils, flax seed oil, evening primrose oil, or CLA, stool will be softened.
• These oils demonstrate anti-inflammatory effects and decrease bloodviscosity.

Hydration. Eight to ten 8-ounce glasses of fluid each day will help keep prevent constipation.

Insoluble fiber.  Three to four times, daily.

Methotrexate side effects may be limited with the use of Taurine

Taurine may be useful in dosages of 3500 mg/day, that is, 7 (500 mg) capsules, daily, for 5 days.

Very inexpensive way to minimize methotrexate toxicity.

Cetiner M, Sener G, Sehirli AO, et al: Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicol Appl Pharmacol. 2005 Nov 15;209(1):39-50.

The efficacy of methotrexate (MTX), a widely used cytotoxic chemotherapeutic agent, is often limited by severe side effects and toxic sequelae. Regarding the mechanisms of these side effects, several hypotheses have been put forward, among which oxidative stress is noticeable. The present study was undertaken to determine whether taurine, a potent free radical scavenger, could ameliorate MTX-induced oxidative injury and modulate immune response. Following a single dose of methotrexate (20 mg/kg), either saline or taurine (50 mg/kg) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the ileum, liver, and kidney were removed to measure malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content, as well as histological examination. Our results showed that MTX administration increased the MDA, MPO activity, and collagen contents and decreased GSH levels in all tissues (P < 0.001), while these alterations were reversed in taurine-treated group (P < 0.05-0.01). Elevated (P < 0.001) TNF-alpha level observed following MTX treatment was depressed with taurine (P < 0.01). Oxidative burst of neutrophils stimulated by phorbol myristate acetate was reduced in saline-treated MTX group (P < 0.001), while taurine abolished this effect. Similarly, flow cytometric measurements revealed that leukocyte apoptosis and cell death were increased in MTX-treated animals, while taurine reversed these effects (P < 0.05). Reduced cellularity in bone marrow samples of MTX-treated group (P < 0.01) was reversed back to control levels in taurine-treated rats. Severe degeneration of the intestinal mucosa, liver parenchyma, glomerular, and tubular epithelium observed in saline-treated group was improved by taurine treatment. In conclusion, it appears that taurine protects against methotrexate-induced oxidant organ injury and inhibits leukocyte apoptosis and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.

Riby JE, Xue L, Chatterji U, Bjeldanes EL, et al: Activation and Potentiation of Interferon-{gamma} Signaling by 3,3'-Diindolylmethane in MCF-7 Breast CancerCells. Mol Pharmacol. 2005 Nov 2;

3,3'-diindolylmethane (DIM), a natural autolytic product in plants of the Brassica genus including broccoli, cauliflower and Brussels sprouts, exhibits promising cancer protective activities, especially against mammary neoplasia in animal models. We observed previously that DIM induced a G1 cell-cycle arrest, and strong induction of cell-cycle inhibitor p21 expression and promoter activity in both estrogen responsive and estrogen independent breast cancer cell lines. We recently showed that DIM upregulates the expression of interferon gamma (IFNgamma) in human MCF-7 breast cancer cells. This novel effect may contribute to the anticancer effects of DIM since IFNgamma plays an important role in preventing the development of primary and transplanted tumors. In this study, we observed that DIM activated the IFNgamma signaling pathway in human breast cancer cells. DIM activated the expression of the IFNgamma receptor (IFNGR1) and IFNgamma responsive genes, p56 and p69-OAS. In cotreatments with IFNgamma, DIM produced an additive activation of endogenous p69-OAS and of an OAS-Luc reporter and a synergistic activation of a GAS-Luc reporter. DIM synergistically augmented the IFNgamma induced phosphorylation of the transcription factor STAT-1, further evidence of DIM activation of the IFNgamma pathway. DIM and IFNgamma produced an additive inhibition of cell proliferation and a synergistic increase in levels of major histocompatibility complex class-1 (MHC-I) expression, accompanied by increased levels of mRNAs of MHC-1 associated proteins and transporters. These results reveal novel immune activating and potentiating activities of DIM in human tumor cells that may contribute to the established effectiveness of this dietary indole against various tumors types.

Dalessandri KM, Firestone GL, Fitch MD, et al: Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer.  Nutr Cancer. 2004;50(2):161-7.

Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3'-Diindolylmethane (DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of absorbable DIM (BioResponse-DIM) supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and a nonsignificant increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.

Garcia HH, Brar GA, Nguyen DH, et al: Indole-3-carbinol (I3C) inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms, and subcellular localization of the CDK2 protein complex. J Biol Chem. 2005 Mar 11;280(10):8756-64. Epub 2004 Dec 20.

Indole-3-carbinol (I3C), a dietary compound found in cruciferous vegetables, induces a robust inhibition of CDK2 specific kinase activity as part of a G1 cell cycle arrest of human breast cancer cells. Treatment with I3C causes a significant shift in the size distribution of the CDK2 protein complex from an enzymatically active 90 kDa complex to a larger 200 kDa complex with significantly reduced kinase activity. Co-immunoprecipitations revealed an increased association of both a 50 kDa cyclin E and a 75 kDa cyclin E immunoreactive protein with the CDK2 protein complex under I3C-treated conditions, whereas the 90 kDa CDK2 protein complexes detected in proliferating control cells contain the lower molecular mass forms of cyclin E. I3C treatment caused no change in the level of CDK2 inhibitors (p21, p27) or in the inhibitory phosphorylation states of CDK2. The effects of I3C are specific for this indole and not a consequence of the cell cycle arrest because treatment of MCF-7 breast cancer cells with either the I3C dimerization product DIM or the anti-estrogen tamoxifen induced a G1 cell cycle arrest with no changes in the associated cyclin E or subcellular localization of the CDK2 protein complex. Taken together, our results have uncovered a unique effect of I3C on cell cycle control in which the inhibition of CDK2 kinase activity is accompanied by selective alterations in cyclin E composition, size distribution, and subcellular localization of the CDK2 protein complex.

Nausea and Vomiting

Nausea and vomiting caused by opioids is very different than nausea caused by chemotherapy & radiation. The difference, however, is irrelevant to the patient. Nausea is one of the most feared side-effects of cancer treatment. Vomiting results in nutritional depletion, and worsening of the overall condition. Nausea & vomiting must be taken very seriously, indeed.

While pain cannot always be relieved entirely, thoughtful pain therapy can reduce pain complaints in nearly all patients. Pain control and amelioration of related symptoms can be expected to improve the quality of life.

David S. Klein, MD, FACA, FACPM, FACMIMS
Director, Pain Center of Orlando
www.suffernomore.com