cancer pain management - medIND

GEHDOO : CANCER MANAGEMENT Indian J. Anaesth. 2006;PAIN 50 (5) : 375 - 390

375

CANCER PAIN MANAGEMENT Dr. R. P. Gehdoo Keywords : Cancer pain, Management. Introduction Pain is one of the most common, unattended and unsolved problem for the cancer patients. Major obstacles or barriers still exist that prevent reduction of pain in cancer patients. Its management is often hindered by barriers created by patients and physicians alike. More over, psychological effects of cancer pain can be devastating. By avoiding potential barriers and understanding the principles of pain management and proper drug selection and titration, one can safely administer adequate pain relief to the patients in need. Education of patients, families, healthcare providers, legislators, and law enforcement agencies is needed to improve the treatment of patients with cancer pain with all the pharmacologic therapeutic modalities available. So there is an immediate need to address these issue at all possible levels. The management of pain is an important goal in the holistic care of patients with cancer Prevalence of cancer pain The incidence of new cancer patients in India is about 10 lakh every year. The incidence of pain in advanced stages of cancer approaches 70% to 80%. One of the major fears of patients with cancer is pain, which can occur as a result of the cancer itself or its treatment, or from other causes1-4. Cancer can spread by metastasis or direct invasion, and 90% of patients with metastasis to osseous structures report pain.5 Studies have shown effective pain control can be achieved in 90% of patients by following the WHO stepladder system. Patients with cancer can have neuropathic pain due to direct compression of nerves or plexus or spinal cord involvement. Surveys have reported that up to 40%– 50% of cancer pain can be categorized as exclusively or partly neuropathic.6,7 Chemotherapeutic drugs such as vinca alkaloids or radiation therapy have also been associated with neuropathic pain. Inadequate treatment and undertreatment are associated with increased pain scores, decreased functional ability, and increased depression and anxiety.8,9 The cancer pain can affect the quality of life in physical, psychological, social as well as spiritual ways. table 1 shows these effects in details. Professor in Anaesthesia Tata Memorial Hospital, Mumbai E-mail:[email protected]

Table 1 - Effect of cancer pain on quality of life a) Physical

: Decreased functional capability, Diminished strength, endurance, Nausea, poor appetite, Poor or interrupted sleep.

b) Psychological : Diminished leisure, Increased anxiety, fear, Depression, personal distress, Difficulty concentrating, Loss of control. c) Social

: Diminished social relationships, Decreased sexual function, affection, Altered appearance, Increased caregiver burden.

d) Spiritual

: Increased suffering, Altered meaning, Reevaluation of religious Beliefs etc.

Barriers to treatment of cancer pain Patient related barriers:- In certain cases, patients themselves create barriers. Finally, some may feel that drugs such as morphine are only for patients who are dying. Many patients fear addiction and or physical dependence. The fact remains that with the treatment of cancer pain, the incidence of addiction in less than 1% of patients. Physical dependence is not the same as psychological addiction. Physical dependence refers to the pharmacologic property of opioids that causes withdrawal, or abstinence syndrome, to occur when the drugs are abruptly discontinued. Symptoms include rhinorrhea, lacrimation, diarrhea, anxiety, yawning, chills, hyperventilation, hyperthermia, muscle aches, vomiting, and feelings of hostility. This syndrome can be avoided by a tapering schedule slowly over a period of time. Physician related barriers:- Physicians may create barriers to effective pain management. An ECOG study explored the most significant barriers to adequate pain management are the physician who treat the pain10. Physicians acknowledge that asking patients about their pain is a critical step to management. However, time constraints and the reluctance of patients hinder adequate pain assessment. Clearly, more education is needed to assist both patients and physicians in the management of cancer pain. The World Health Organization (WHO) has stated that “nothing would have a greater impact on improving cancer pain treatment than implementing existing knowledge” Causes of cancer pain The two most common causes of cancer pain are the cancer itself and it’s treatments.

PG ISSUE : PAIN

376

INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2006

The cancer itself - Cancer causes pain, probably by the pressure on one of the body’s organs or on bone or nerves or on blood vessels. Cancer treatments - There are a variety of treatments for cancer and some of them are less than pleasant. Some examples of treatment-related pain include: i) Chemotherapy produces numerous side effects that cause pain like mucositis, peripheral neuropathy, constipation, diarrhea, nausea, vomiting and abdominal cramps. ii) Radiotherapy also similarly produces pain due to mucositis, peripheral neuropathy, burning sensations etc. iii) Surgical treatments apart from producing acute post-operative pain, it can also produce long term post amputation phantom limb pain, stump pain, post-mastectomy pain etc. Assessment of cancer pain Proper assessment of pain in the cancer is imperative because it’s failure can lead to an under-treatment. The critical role of the assessment of cancer pain was highlighted in a 1993 study by Von Roenn JH et al.10 According to this study, poor pain assessment was the greatest barrier to the effective cancer pain management. Because of the multiple causes of pain, careful evaluation of pain is required. Careful and comprehensive assessment of cancer pain is essential in finding the best treatment for the pain. Visual analog and 0 to 10 point numeric scales are used to measure pain, a process that allows frequent reassessment and therefore adequate treatment. If the patient understands the scale and is capable of answering and if end points and adjective descriptors are carefully selected, each of these instruments can be valid and reliable11,12 Some of the scales to measure pain are shown in table 2 as follows. Table - 2 : Different Pain measurement scales used in the cancer patients. Simple Descriptive Pain Distress Scale None

Annoying

Uncomfortable

Dreadful

Horrible

Agonizing

Initial assessment should be done at the new report of pain and should focus on identifying the cause of the pain and it’s management plan. Subsequent assessments should evaluate the effectiveness of the plan and, if pain is unrelieved, determine whether the cause is related to the progression of disease, a new cause of pain, or the cancer treatment. Patients self-report about the pain should be the primary source of assessment. Self-report should include a description of the pain; its location, intensity/severity, and aggravating and relieving factors; and the patient’s cognitive response to pain. Neither behavior nor vital signs should be used in lieu of a self-report One routine clinical approach to pain assessment and management is summarized by the mnemonic “ABCDE”: A.

Ask about pain regularly. Assess pain systematically.

B.

Believe the patient and family in their reports of pain and what relieves it.

C.

Choose pain control options appropriate for the patient, family, and setting.

D.

Deliver interventions in a timely, logical, and coordinated fashion.

E.

Empower patients and their families. Enable them to choose the modality.

Elements of Cancer Pain Assessment are summarized in the table 3 as follows Factor

Question

Intensity

How severe is your pain?

Character

How would you describe your pain?

Location

Where is your pain?

Radiation

Does your pain go anywhere else?

Timing

When does your pain occur?

Correlated factors

What makes your pain better or worse?

|_________|______________|______________|___________|__________| 0-10 Numeric Pain Distress Scale No pain

Distressing pain

Unbearable pain

|______|______|______|______|______|______|______|______|______|______| |

|

|

|

|

|

|

|

|

|

|

0

1

2

3

4

5

6

7

8

9

10

Visual Analog Scale (VAS) No distress

Unbearable distress

|___________________________________________________________________| |

10

Implications of pain How does this pain affect your daily living? Meaning of the pain What does the pain mean to you? The initial evaluation of pain must include • A detailed history, including an assessment of the pain intensity and character. •

Physical examination, emphasizing the neurological examination.

GEHDOO : CANCER PAIN MANAGEMENT

• •

Psychosocial assessment. Appropriate diagnostic and investigative workup to find out the cause of the pain.

A psychosocial assessment should emphasize the effect of pain on patients and their families, as well as patients’ preferences among pain management methods. Pain management schedule Following are the different modalities by which the cancer pain can be managed reasonably well so as to ensure a good quality of life for the patient till the end of life. i) Palliative : Deep X-rays, RT / CT, tumor excision etc. ii) Pharmacotherapy : Analgesics and adjuvants iii) Injection Techniques : Somatic & sympathetic Nerve blocks. Intrathecal / Epidural neurolytics : Cryo-analgesia ii) Neuroablative tech.: Radiofrequency denervation, Pituatory injection of alcohol iii) Neuro-stimulatory Techniques : TENS, DCS, PAGS iv) Complementary / Alternative Approaches : Massage, Hot /cold sponges. v) Psychological Interventions. vi) Lifestyle Changes : YOGA, Biofeedback, relaxation. vii) Rehabilitative approaches 1) Pharmacotherapy of cancer pain Pharmacotherapy plays a very vital role in the management of cancer pain, as almost 80 - 90% of the pain can be reasonably controlled using different analgesics along with the adjuvant. The success with the use of pharmacotherapy depends up on the proper use of medications in the recommended formats. A simple, well-validated, and effective method for assuring the rational titration of therapy for cancer pain has been devised by WHO.13 It has been shown to be effective in relieving pain for approximately 90 percent of patients with cancer and over 75 percent of Fig. cancer patients who are terminally ill.14 The World Health Organization (WHO) in 1986 established a stepladder approach for treatment of patients with cancer pain (fig.). The goal for this ladder was to provide treatment guidelines that healthcare practitioners could easily follow. The five essential concepts in the WHO approach to drug therapy of cancer pain are : i) By the mouth. ii) By the clock. iii) By the ladder. iv) For the individual. v) With attention to detail. The first step in this ladder is the use of acetaminophen, or other NSAIDs for mild to moderate pain. Adjuvant drugs to enhance analgesic efficacy, or to treat concurrent symptoms that exacerbate pain may be used at any step.

377

When pain persists or increases an opioid such as codeine or hydrocodone should be added (not substituted) to the NSAID. Opioids at this step are often administered in fixed dose combinations with acetaminophen because this combination provides additive analgesia.15 Pain that is persistent, or moderate to severe, should be treated by using more potent opioid or using higher dosages as shown in the third step. At this step separate dosage of opioid and nonopioid analgesic should be used to avoid the overdoses of acetaminophen or NSAID. Opioids like morphine, hydromorphone, methadone or fentanyl are use din this step. A) NSAIDs, COX-2 Inhibitors, ASA, and Acetaminophen An NSAID alone may be effective for mild cancer pain. It acts centrally by inhibiting the COX-2 production and thereby reducing the prostaglandin synthesis. A similar action is also seen at the site of inflammation in the peripheral tissues. They also have antipyretic and anti-inflammatory activity. It is now established that prostanoids play important roles in many cellular responses and pathophysiologic processes, including modulation of inflammatory reactions, erosion of cartilage and juxta-articular bone, gastrointestinal cytoprotection and ulceration, angiogenesis and cancer, hemostasis and thrombosis, renal hemodynamics, and progression of kidney disease.16 NSAIDs play a key role in the first step of the WHO guidelines for management of cancer pain. Nearly 90% of patients with bone metastasis present with pain.9 NSAIDs are the most effective agents for treating such a pain. Comparison of opioid combination preparations with NSAIDs alone showed no or at most only a slight difference which was not statistically significant.9,17,18,19 NSAIDs also have a ceiling analgesic effects, which many a times becomes a limiting factor. NSAIDs, cyclooxygenase type 2 (COX-2) inhibitors, and acetylsalicylic acid prevent formation of prostanoids from arachidonic acid. This synthesis of prostaglandins is controlled by two separate cyclooxygenase enzymes (COX-1 and COX-2). Traditional nonselective NSAIDs inhibit both COX-1 and COX-2, that results in not only an anti-inflammatory response but also reduced gastrointestinal cytoprotection; leading to the gastric ulceration and bleeding. Newer COX-2 inhibitors selectively inhibit only this enzyme, thus maintaining an anti-inflammatory response with low risk of side effects that occur with nonselective inhibitors of COX enzymes.16,18 Recently, however, COX-2 inhibitors have received attention because of an increased incidence of stroke and myocardial infarction when used in high doses.20

378

PG ISSUE : PAIN


The commonest side effects encountered with the use of NSAIDs are peptic ulcerations, gastric erosions, nausea, vomiting, bleeding diathesis, thrombocytopenia, retention of water and salt, and hepato-renal dysfunction. Dosing data for acetaminophen and NSAIDs Drug

Usual dose for patients > 50 kg body weight

Usual dose patients < 50 kg body weight

Acetaminophen

650 mg q 4 h 975 mg q 6 h

10-15 mgkg-1 q 4 h 15-20 mgkg-1 q 4 h (rectal)

Ibuprofen

400-600 mg q 6 h

10 mgkg-1 q 6-8 h5

Ketorolac tromethamine

60 mg initially, then 30 mg q 6 h Intramuscular dose not to exceed 5 days

B) Opioids In treating patients with moderate to severe cancer pain, opioids (in particular morphine) is the mainstay and gold standard with which other treatment modalities are compared.4,21,22 In 1973, several teams of researchers found the presence of an “opioid receptor” in the nervous system23 .It was believed that endogenous substances present in the body which when released are bound to the opioid receptor and provide analgesia. This receptor binding can be reversed by naloxone. These endogenous substances were later identified as enkephalins, ß-endorphins, and dynorphin. Three separate opioid receptors were identified as: mu ( ), kappa (K), and delta (d). The major receptor associated with analgesia is mu, and opioid development has centered on targeting this site, which provides intense analgesia without binding other opioid receptors that are commonly associated with unwanted side effects (eg, nausea and dysphoria). They act at the central as well as spinal cord level. They stimulate the chemoreceptor trigger zone in the brain, thereby inducing vomiting sensations and depress respiratory and vasomotor centre also. Morphine This is the most popular and extensively used opioid, which has an immense analgesic action. It is available as oral tablets (immediate and sustained release tablets), syrup as well as injectable form for Intramuscular, subcutaneous, intravenous, intrathecal and epidural route. Opioids do not have any ceiling effects, so they can be escalated to a very high dose levels also. Morphine can be started at 10 mg thrice daily doses and if needed, can be escalated to even 200-800 mg daily on a divided dose basis. Another important principle of management is to individualize the approach to each patient. There is no standard dose or acceptable range. Doses should be titrated according to pain relief as reported by the patient. Most patients require the equivalent of 40 to 400 mg of morphine per 24 hours, but some require much larger amounts

Another alternative to oral opioid use is rectal administration. This route can be very helpful for patients with nausea, vomiting, bowel obstruction, or malabsorption. Rectal opioid administration can eliminate the need for insertion of needles and use of portable pumps. The bioavailability of morphine administered rectally varies considerably among individuals.24 Alternatives to oral morphine For some patients, side effects of oral morphine persist for a longer period and are problematic, and an alternative opioid analgesic can be tried as mentioned below. Oxycodone is a pure opioid agonist with an activity profile similar to that of morphine. It is available either as a component of fixed-dose combinations that include aspirin or acetaminophen or as a single agent. It is given in the doses of 30 mg orally either twice or thrice daily. Fentanyl, an analgesic commonly used in anesthesia, is now widely used transdermal or transmucosal delivery systems with predictable drug concentration comparable to that achieved via the intravenous route. It is available as 25, 50 and 100 mcg transdermal patches, to be applied on a non-hairy skin. Action usually starts within a couple of hours and reaches peak levels within 18 – 24 hours, while effect lasts for almost 72 hours. It is found that transdermal fentanyl patch is associated with reduced gastrointestinal toxicity, constipation, nausea and better patient’s tolerance as well as acceptance.25,26 However, the cost of transdermal fentanyl may be a significant factor Side effects : Potential side effects of opioids include sedation, nausea, constipation, myoclonus, and respiratory depression. Tolerance to opioid-induced sedation usually develops within a few days. Increased doses in the chronic users of opioids can continue to provide adequate analgesia as there appears to be no ceiling, but escalating doses can increase side effects (eg, nausea, vomiting, constipation, abdominal pain, pruritus) that may limit their use.8,27 Long-term use of opioids is associated with physical dependence and tolerance. These two physiologic processes have nothing to do with addiction, which is psychological. Rotating opioids reduces tolerance. Addiction is a process believed to be a psychological and behavioral syndrome manifested by drug-seeking behavior, loss of control over drug use, and continued use despite adverse effects. In is reported that addiction is rarely seen in patients with cancer pain when use is


appropriate; however, patients with a history of previous addiction may be at an increased risk for this. Doses for opioid analgesics Drug

Morphine

Usual Starting Dose for Mod. to Severe Pain Oral

Parenteral

30 mg q 3-4 h

10 mg q 3-4 h

Morphine, controlled release

90-120 mg q 12 h

N/A

Hydromorphone

6 mg q 3-4 h

1.5 mg q 3-4 h

Methadone

20 mg q 6-8 h

10 mg q 6-8 h

Codeine (with acetaminophen)

60 mg q 3-4 h

60 mg q 2 h (IM/SC)

Oxycodone

10 mg q 3-4 h

N/A

C) Adjuvant analgesia Adjuvant analgesics are defined as drugs with a primary indication other than pain that have analgesic properties in some painful conditions. The group includes numerous drugs in diverse classes. They usually are combined with an opioid in the cancer pain management. Some adjuvant analgesics are useful in several painful conditions like antidepressants, corticosteroids, a2-adrenergic agonists, neuroleptics etc., whereas others are specific for neuropathic pain (anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists), bone pain (calcitonin, bisphosphonates, radiopharmaceuticals), musculoskeletal pain (muscle relaxants), or pain from bowel obstruction (octreotide, anticholinergics). i) Ketamine (N-methyl-D-Aspartate receptor blockers) Antagonists at the NMDA receptor may offer another novel approach to the treatment of neuropathic pain in cancer patients. Interactions at the N-methyl-D-aspartate (NMDA) receptor are involved in the development of CNS changes that may underlie chronic pain and modulate opioid mechanisms, specifically tolerance.28 Ketamine, is a NMDA receptor antagonists, administered by intravenous infusion or orally, is effective in relieving cancer pain29,30,31,32 and reducing opioid requirements. It has been shown to attenuate and reverse morphine tolerance by inhibition of NMDA receptors.33 Low-dose continuous intravenous administration of ketamine can provide analgesia with a minimum incidence of associated cardiovascular or neurologic side effects33,34. Infusion rates of 0.1 to 0.15 mgkg-1hour-1 titrated to sedative effects have been used to treat patients with refractory pain resistant to opioid therapy. During titration, opioid consumption can be slowly reduced. The dose can be gradually escalated, with close monitoring of pain and side effects. For patients with

379

refractory pain and limited life expectancies, long-term therapy can be maintained using continuous subcutaneous infusion. Tachyphylaxis can develop with prolonged use of ketamine, and bioavailability from oral administration can also limit long-term effectiveness.3 ii) Antidepressants Tricyclic antidepressants (TCAs) have efficacy in treatment the neuropathic pain and associated comorbid depression. The doses effective for neuropathic pain are usually lower than those used for depression. In this group, both tertiary amines (amitriptyline hydrochloride, imipramine) and secondary amines (nortriptyline hydrochloride and desipramine hydrochloride) have analgesic effects in cancer patients, especially for concurrent neuropathic pain syndrome.35 The major mechanism of the analgesic effect was believed to be related to inhibition of norepinephrine or serotonin reuptake or of both. Common side effects include sedation, confusion, orthostatic hypotension, weight gain, tachy- arrhythmias, anticholinergic effects (dry mouth, blurred vision, and urinary retention). TCAs should be administered cautiously in the elderly and in patients with glaucoma, benign prostatic hypertrophy, cardiovascular disease, or impaired liver function. In general, secondary amines have fewer sedative and anticholinergic effects than tertiary amines; therefore, the secondary amines may be more desirable in the elderly.36 In this latter population, the starting dose is usually 10 mg every night, then gradually titrated to therapeutic level. Recent clinical trials demonstrate that the selective serotonin and norepinephrine reuptake inhibitor duloxetine hydrochloride, an antidepressant, is also effective for neuropathic pain.37 iii) Anticonvulsants There is good evidence that the anticonvulsant drugs are useful in the management of neuropathic pain.38,39,40 Anticonvulsants have been used in the treatment of neuropathic pain for many years. The mechanism of the analgesic activity of them is thought to be associated with blocking sodium channels and increased membrane stability. Among the older drugs, evidence of efficacy is best for carbamazepine and phenytoin, and both valproate and clonazepam have been widely used. The classic indication for carbamazepine is trigeminal neuralgia38 and the use of phenytoin in cancer pain has been described. The most common adverse effects are dizziness, somnolence, ataxia, and lethargy. Caution should be taken when administering these drugs because of their severe adverse effects like bone marrow depression and liver toxicity. Baseline evaluation of liver function and a complete blood cell count

380

PG ISSUE : PAIN

should be done before initiating use of these medications. Due to their frequent side effects, the use of these drugs has declined with the introduction of the newer analgesic anticonvulsants. Gabapentin and pregabalin are the latest additions in this group. These drugs are very effective in trigeminal neuralgia, post-herpetic neuralgia and diabetic peripheral neuropathic pain. At present, gabapentin is the most commonly used adjuvant analgesic for neuropathic pain.41 It is not metabolized, and has the most acceptable safety profile for side effects. Treatment usually starts with 100 mgd-1 to 300 mgd-1. Gradual dose titration continues until benefit occurs, side effect supervenes, or the total daily doses reach 3600 mg. An adequate trial should include 1 to 2 weeks. Beneficial analgesic role of gabapentin has been established in several types of nonmalignant neuropathic pain42-47 and it is now widely used to treat cancer-related neuropathic pain. The most common adverse effects are somnolence, dizziness, and unsteadiness. If titrated carefully, gabapentin is usually well tolerated.48 Like gabapentin, pregabalin have proven efficacy for neuropathic pain. It is a new anticonvulsant with a mechanism identical to that of gabapentin and strong evidence of analgesic efficacy.49 Pregabalin is usually given in the doses of 75 – 150 mg twice daily. iv) Corticosteroids Corticosteroids possess analgesic properties in a variety of cancer pain syndromes like bone pain, neuropathic pain from infiltration or compression of neural structures, headache due to increased intracranial pressure, and pain due to obstruction of a hollow viscus (e.g., bowel or ureter) or to organ capsule distention. Corticosteroids produce their effects by (1) inhibiting prostaglandin production and reducing inflammation (2) decreasing capillary permeability and reducing peritumor edema; and (3) directly affecting membrane stabilization, which decreases neuronal excitability. Dexamethasone : is most commonly used for metastatic spinal cord compression because of a decreased tendency for salt and fluid retention.50 and an effective management of associated pain and symptoms,51 while awaiting more definitive treatment, if justified by the goals of care. The doses range from 10 mg to 20 mg administered intravenously (IV) every 6 hours. Prednisone and methylprednisolone:- can also be used. On the basis of clinical experience, corticosteroids are usually administered either in a high-or a low-dose regimen. A high-dose regimen (e.g., dexamethasone, 100 mg, followed initially by 96 mg/day in divided doses) has


been used for patients who experience spinal cord compression or an acute episode of severe pain that cannot be promptly reduced with opioids52 The dose can be tapered over days or weeks after the initiation of other analgesic approaches (e.g., opioid therapy, radiation therapy). A low-dose corticosteroid regimen (e.g., dexamethasone at a dose of 2–4 mg once or twice daily) can be used for patients with advanced cancer who continue to have pain despite optimal dosing of opioid drugs. Corticosteroid drugs have several other indications. They can improve appetite, nausea, malaise, and overall quality of life.52-55 Although the risk of adverse effects increases with both the dose and duration of therapy, long-term treatment with relatively low doses is generally well tolerated. Repeated assessments are required to ensure that benefits are sustained. Long-term corticosteroid therapy may increase the risk of peptic ulcer disease.56 The concurrent administration of an NSAID and a corticosteroid increases the risk of peptic ulcer disease substantially; and administration of a gastroprotective drug can be justified if it is used. Other significant adverse effects are hypertension, hyperglycemia, immuno-suppression, gastrointestinal ulceration, and psychiatric disorders. v) a2-Adrenergic agonists Although clonidine and tizanidine are 2-adrenergic agonists and may be considered nonspecific multipurpose adjuvant analgesics, the supporting data are limited and the potential for side effects, like somnolence and hypotension, is relatively great. Fewer than one-fourth of patients are likely to respond to systemic administration of clonidine.57 Intraspinal clonidine has been shown to reduce pain (especially neuropathic pain) in patients with severe intractable cancer pain partly responding to opioids.58 Tizanidine is approved as an antispasticity agent. Although the evidence of the analgesic efficacy of tizanidine is limited to the treatment of myofascial pain syndrome59,60 and the prophylaxis of chronic daily headache. As it is more specific for the2-adrenergic receptor than clonidine, hypotension occurs less commonly. vi) Adjuvant analgesia for bone pain Bone pain is a common problem in the palliative care setting. It is usually secondary to tumor expansion and inflammation. Radiation therapy along with corticosteroids is highly effective for the treatment of patients with focal bone lesions. Multifocal bone pain may benefit from treatment with an NSAID or a corticosteroid. Other adjuvant analgesics that are potentially useful in this setting include calcitonin, bisphosphonate compounds, and selected radiopharmaceuticals.


Bisphosphonates Bisphosphonates are analogues of inorganic pyrophosphate that inhibit osteoclast activity and, consequently reduce bone resorption in a variety of illnesses. Pamidronate has been extensively studied and has well established analgesic efficacy in populations with bone metastases.61 Its analgesic effects have been shown in breast cancer62,63 and multiple myeloma.64 The dose usually recommended is 60–90 mg i.v. (infused over 2–4 hours) every 3–4 weeks.63 The reduction of skeletal morbidity (pathological fractures, need for bone radiation or surgery, spinal cord compression, hypercalcemia) described with the administration of pamidronate in multiple myeloma and breast cancer patients is another incentive to use it as an adjuvant. Adverse effects, including hypocalcemia and a flu-like syndrome, which are dose related and typically transitory. Nephrotoxicity occurs rarely, and is transitory. Zoledronic acid (Zometa) is a new bisphosphonate that is approximately two to three times more potent than pamidronate. It has been shown to reduce pain and the occurrence of skeletal-related events in breast cancer,64-66 prostate cancer and multiple myeloma64 as well as a variety of solid tumors, including lung cancer.67 It is effective in both osteoblastic and osteolytic lesions.66 It is as effective as pamidronate and its use is more convenient, as it can be infused safely over 15 minutes at a dose of 4 mg every 3 weeks. The side effects are similar to those encountered with pamidronate, and the dose need not be adjusted in patients with mild-to-moderate renal failure.68 Calcitonin may have several pain-related indications in the palliative care setting, including pain from bone metastasis. 69 Calcitonin is usually administered subcutaneously and intranasally. The initial dose is 200 IU in one nostril a day, and alternating nostrils every day. Periodic monitoring of calcium and phosphorus is prudent during treatment. Apart from infrequent hypersensitivity reactions associated with subcutaneous injections, the main side effect is nausea. Radiopharmaceuticals Radionuclides that are absorbed at areas of high bone turnover have been assessed as potential therapies for metastatic bone pain19 Strontium-89 and samarium-153, are commercially available, and found to be effective as monotherapy or as an adjunct to conventional radiation therapy70,71 Given the potential for myelosuppression associated with their use, these drugs usually are considered when pain is refractory to other modalities.

381

vii) Oral and parenteral local anesthetics Local anesthetics have analgesic properties in neuropathic pain.72 Due to their potential for serious side effects, they have been conventionally positioned as secondline therapies, reserved for the treatment of severe intractable or ‘crescendo’ neuropathic pain. These agents should be considered once trials of anticonvulsants or antidepressants have failed. Common adverse effects are paresthesias, abnormal taste, tinnitus, blurred vision, drowsiness or local skin rash secondary to topical application of the anesthetic. Severe systemic toxicity due to high plasma levels can cause seizure or result in cardiotoxicity with cardiac arrest. Despite negative results obtained in randomized controlled trials in neuropathic cancer pain.73 Clinical experience justifies considering its use. Brief infusions can be administered at varying doses within the range of 1–5 mgkg-1 infused over half to two hours. Mexiletine hydrochloride, an antiarrhythmic with structural similarity to lidocaine, has been used to treat patients with neuropathic pain from numerous etiologies and is the preferred oral local anesthetic. Controlled studies of mexiletine have demonstrated a relatively high rate of adverse effects (nausea, vomiting, tremor, dizziness, unsteadiness, and paresthesias) and discontinuation due to toxicity in almost one-half of patients.74 viii) Topical analgesics lidocaine 5% patch - This formulation is useful for the treatment of postherpetic neuralgia75 and clinical experience supports its use for other neuropathic pain conditions. 5% of lidocaine gel or patch is placed directly on skin over painful regions The patch is usually applied 12 hours per day, but a few studies indicate a high level of safety with up to three patches for periods up to 24 hours76 The most frequently reported adverse event is mild to moderate skin redness, rash, or irritation at the patch application site. Capsaicin is the ingredient in chili pepper that produces its pungent taste. When applied topically, it causes the depolarization of the nociceptors and release of substance P. Regular use eventually leads to depletion of substance P from the terminals of afferent C-fibers, potentially leading to decreased pain perception. In cancer patients, capsaicin cream has been shown to be effective in reducing neuropathic postsurgical pain (such as postmastectomy pain).77 There are two commercially available concentrations (0.025% and 0.075%), to be applied three to four times daily. A trial of several weeks is needed to adequately judge effects. A major side effect, localized irritation that causes a burning sensation, limits use of capsaicin.

382

PG ISSUE : PAIN

ix) Miscellaneous adjuvants Baclofen : It is an agonist at the gamma aminobutyric acid type B (GABAB) receptor, has established efficacy in trigeminal neuralgia78 and is often considered for a trial in any type of neuropathic pain. The effective dose range is very wide (20 mgday-1 to >200 mgday-1 orally), and titration from a low initial dose is necessary. The possibility of a serious withdrawal syndrome on abrupt discontinuation must be avoided by a gradual dose taper. It is also used in treatment of spasticity and central pain secondary to spinal cord lesions. Benzodiazepines : Evidence of analgesic effects of benzodiazepines is limited and conflicting, and overall it provides little support for the conclusion that these drugs are analgesic for neuropathic pain.79 Nonetheless, a trial of clonazepam can still be justified in refractory neuropathic pain on the basis of anecdotal experience, especially in the case of the common coexistence of pain and anxiety. Psychostimulants : There is substantial evidence that psychostimulant drugs dextroamphetamine, methylphenidate and caffeine have analgesic effects80 In cancer patients, methylphenidate can reduce opioid-induced somnolence, improve cognition, treat depression, and alleviate fatigue.81 Treatment is typically begun at 2.5–5 mg in the morning and again at midday, if necessary, to keep the patient alert during the day and not interfere with sleep at night. Doses are increased gradually until efficacy is established. Hormonal therapy : For breast or prostate cancer pain, hormonal therapy (eg, tamoxifen citrate) can provide beneficial effects. Antihistamines, anticholinergic drugs, antipsychotics, and laxatives : are also used to treat patients for cancerrelated symptoms or complications of cancer treatment, such as dizziness, vertigo, nausea and vomiting, confusion and delirium, and constipation. This group of medications should be used cautiously, with precautions taken to reduce side effects and drug-drug interactions. Injections of botulinum toxin:- can be considered for refractory musculoskeletal pain related to muscle spasms82 including those occurring after radiation therapy.83 x) Adjuvants used for pain caused by bowel obstruction The management of symptoms associated with malignant bowel obstruction may be challenging. If surgical decompression is not feasible, the need to control pain and other obstructive symptoms, including distension, nausea, and vomiting, becomes paramount. The use of opioids may be problematic due to dose-limiting toxicity (including gastrointestinal toxicity). Anecdotal reports suggest that anticholinergic drugs, the somatostatin analogue octreotide (Sandostatin), and corticosteroids may be useful adjuvant analgesics in this setting.


Octreotide The somatostatin analogue octreotide inhibits the secretion of gastric, pancreatic, and intestinal secretions, and reduces gastrointestinal motility. These actions, which can occur more rapidly than similar effects produced by anticholinergic drugs, probably underlie the analgesia and other favorable outcomes that have been reported in case series and one randomized trial84 in patients with bowel obstruction. Octreotide has a good safety profile. Adjuvant analgesic drugs for cancer pain. Drug

Approx. adult daily dose range

Route of administration

Dexamethasone

16-96 mg

PO, IV

Prednisone

40-100 mg

PO

Carbamazepine

200-1,600 mg

PO

Phenytoin

300-500 mg

PO

Amitriptyline

25-150 mg

PO

Lidocaine

5 mgkg-1

IV/SC

Mexiletine

450-600 mg

PO

Dextroamphetamine

5-10 mg

PO

Methylphenidate

10-15 mg

PO

2) Nonpharmacologic and complementary approaches Nonpharmacologic interventions are important adjuncts to treatment modalities for patients with cancer pain. A variety of modalities can be used to reduce pain and concomitant mood disturbance and increase quality of life. Pain is a multifaceted phenomenon that involves biological, psychological, and social consequences. The biopsychosocial model encompasses biological, psychological, and social aspects of care and has been applied to patients with cancer pain85. Few of the important and useful nonpharmacologic and complementary medicine modalities in the cancer pain management are discussed underneath. a) Physical modalities Specific physical modalities often used to augment pain treatment plans are the rehabilitative plans such as optimizing range of motion, strength, endurance, and neuromuscular control can reduce instability and pain associated with disuse.86 Another common physical treatment modality, transcutaneous electrical stimulation (TENS), delivers mild electrical stimulation to painful regions, while application of heat or cold or a combination of both is also used. The heat application method is often used to alleviate postoperative pain and pain from inflammatory processes associated with cancer. Finally, therapeutic exercise and massage can be used to improve range of motion and reduce muscle tension, respectively.


b) Psychological Interventions Cancer pain can be intensified by psychological distress, especially mood disturbance, depression, fear, and anxiety as shown by the large majority in 19 studies reviewed by Zaza and Baine.87 Fear of disease progression and a painful death is common. Psychiatric disorders for which patients need treatment are common in cancer, but appear to be more prevalent in patients with cancer who report significant pain.88 Therefore, early consultation with a mental health professional that can diagnose and treat psychiatric disorders (eg, major affective disorders, adjustment disorders, and anxiety disorders) is important. c) Behavioral interventions Behavioral therapy involves analysis of behavior that has been learned or conditioned for evaluation, prevention and treatment of pain or psychological distress. Psychophysiologic interventions such as biofeedback and relaxation have been categorized as behavioral. Combination strategies include meditation, hypnosis, music therapy, and systematic desensitization. The latter pairs relaxation with exposure to stimuli that produce anxiety; it can result in controlling anxiety. Hypnosis:- Hypnosis is a complex process of attentive, receptive concentration characterized by a modified sensorium, altered psychological state, and minimal motor functioning.89 It is an especially focused state of concentration that can be used to alter painful sensations. Hypnosis has been used to successfully relieve nausea and vomiting associated with chemotherapy.90 Meditation and yoga : are also found to be beneficial in few cancer pain cases. d) Complementary medicine It has been found that complementary treatment modalities have some supportive empirical evidence or promising preliminary data in the areas of traditional Chinese medicine treatment modalities and mind-body medicine as described below. Traditional chinese medicine Acupuncture : Traditional Chinese medicine dates back more than 4000 years and regards health as a balance between individual and environment. Acupuncture, acupressure, and electroacupuncture are forms of traditional Chinese medicine. Pressure on certain meridian points can be exerted by insertion of small-gauge needles (eg, acupuncture) or a combination of needles and lowfrequency electric current (electroacupuncture), or by manual pressure with a finger (acupressure).89 Evidences indicates that effects of acupuncture are due to release of multiple endogenous substances (eg, steroids and endorphins) that no single drug treatment could mimic.

383

Acupuncture has been found to help manage a wide variety of pain conditions. Evidence is particularly strong for acupuncture in acute pain, though limited evidence exists for postprocedure pain in patients with cancer. A randomized controlled trial of auricular acupuncture for patients with cancer found substantial pain reduction in patients receiving acupuncture compared with those receiving placebo91 Side effects of acupuncture, acupressure, and electroacupuncture are generally limited to minor bruising or irritation at the point of contact. 3) Radiation and chemotherapy a) Radiation Radiation, which is used to treat cancer, can also be helpful in alleviating cancer pain in some circumstances. It can be used to reduce the size of some tumors which, in turn, takes pressure off organs and nerves and relieve pain. It can also be used to treat the pain of cancer that has spread to the bones, the brain, blood vessels, nerves and spine. Radiation can also be the cause of pain for cancer patients due to side effects like skin irritation and redness. Additional possible side effects vary, depending on the area of the body receiving the radiation, and the form in which it is administered. b) Chemotherapy Chemotherapy, which is used primarily to treat cancer, can also sometimes be helpful in reducing the size of the tumors and thereby easing pain. Chemotherapy can also be the cause of pain for cancer patients due to side effects like stomatitis, peripheral neuropathies, constipation, nausea, vomiting and anorexia. 4) Surgery and special procedures Palliative Surgery and other non-medication special procedures are useful tools to treat some forms of cancerrelated pain. Surgery itself can reduce the size of tumors (Debulking), move tumor out of the path of obstructing the digestive system, alleviate pressure on nerves, drain fluids related to cancer growth (ascites). Sometimes surgery is also used to stabilize bones that have been treated by radiation or chemotherapy to reduce metastases. 5) Special procedures Special procedures includes a variety of painrelieving methods. Some special procedures used to treat cancer pain include: Neurolytic neural blockade Neurolytic nerve blocks are used to interrupt the pain pathway. The possibility of controlling otherwise intractable pain by the relatively brief application of a local anesthetic or neurolytic agent makes neural blockade an attractive approach in selected patients. Patient selection

384

PG ISSUE : PAIN

and timing of neural destruction for pain relief are based on the exhaustion of more conservative modalities, a lack of available, clinically superior options, and the availability of capable physician and support systems after the procedure. A properly executed neurolytic nerve blockade may reduce the requirements of the opioids. Indications for Neurolytic nerve blockade are as follows • Management of chronic and intractable pain that is not responsive to other modalities; •

Treatment of cancer pain in patients with short life expectancy (less than a year); and

•

Alternative management to treat spasticity in order to improve balance, gait, self-care, and global rehabilitation. Advantages :- The neurolytic blocks have the following advantages •

Neurolytic blocks provide longer duration of pain relief.

•

Drugs and inexpensive equipment required are readily available.

•

Elaborate equipment is not mandatory.

•

Long-term indoor ward treatment is avoided,

•

Frequent visits to the pain center are not required.

•

Patient can remain at home pain free even in areas where medical help is scarce.

Disadvantages : The neurolytic blocks are known to have the following disadvantages: •

The blocks are occasionally unpredictable.

•

Complications like paresis of muscles are known.

•

Blocks are to be repeated after 6-8 weeks.

•

Elaborate equipment like CT-Scan, C-arm, or image intensifier is needed for accuracy.

•

Some patients have to be kept in the hospital for 1-2 days to assess the pain relief and to treat the transitory complications.

Neurolytic agents Alcohol :- is commercially available as a colorless solution that can be injected readily through small bore needles, and is hypobaric (0.85)with respect to cerebrospinal fluid. Depending on the site of injection and the concentration of alcohol, administration is accompanied by a variable degree of discomfort and complications. It is generally used undiluted (absolute). 50% alcohol is used specially for celiac plexus blockade.


Phenol :- Various concentrations (3%, 6% ) of phenol prepared with saline, water, glycerine and different radiologic dyes have been advocated. Phenol is relatively insoluble in water. Phenol mixed in glycerine is hyperbaric (1.05-1.1) with respect to cerebrospinal fluid but is so viscous that, even when warmed, injection is difficult through needles smaller than 20-gauge. Shelf life is approx. 1 year. Less commonly, ammonium sulfate and chlorocresol are utilized to produce neurolysis. Peripheral blockade Peripheral neurolysis has a definite role in the management of cancer pain. To ensure effective analgesia, neural interruption is planned proximal to the source of irritation. Because the sensory distribution of peripheral nerves overlaps, blockade of neighboring segments is recommended. Many peripheral nerves are of mixed type. Firstly, a diagnostic block with local anesthetic is essential to evaluate the impact of concomitant motor deficit. In performing a peripheral neurolytic block, accuracy is essential for good results and to avoid damage to nontargeted structures. This is particularly true in the cervicofacial region, where abundant neuro-vascular structures are present. Cranial nerves such as Trigeminal and Glassopharyngeal nerves are often blocked by neurolytic drugs in advanced cancers of head and neck. Even intercostals nerves are blocked for the pain arising from the chest wall and intrathoracic malignancies. Blockade of the thoracic sympathetic chain is a useful diagnostic and therapeutic procedure for identifying segmental nociceptive pathways, which may be causing pain due to inflammatory, infectious (herpes zoster), or structural pathology. Subarachnoid and Epidural neurolytic blocks :(Central neuraxial blockade) Small volumes of alcohol or phenol may be injected intrathecally to destroy nerve root function in a localized distribution. Approximately 60 percent of patients treated with intraspinal alcohol or phenol experience complete or near-complete relief of pain until death.92 The advantages of neuroaxial neurolysis are (1) a high proportion of good results in properly selected cases; (2) ease of performance with minimal requirements for equipment; (3) minimal or no hospitalization; (4) duration of pain relief in preterminal state of the patients; (5) ease of repetition if needed; (6) suitability for aged or debilitated patients; and (7) a low complication rate when proper technique is observed.


Complications including paresis, paralysis, and bowel or bladder dysfunction affect 0.5 to 2 percent of patients treated with intraspinal alcohol or phenol. An epidural injection of phenol (or alcohol) can accomplish the same goal; however, the targeting of the injectate is less precise, the neurolytic effects take place over a more diffuse area than that affected by the intrathecal route, and the technique is less well established than intrathecal injection.93 Subarachnoid Vs. Epidural neurolysis Subarachnoid neurolysis offers the following potential advantages over the epidural techniques. -

Return of CSF verifies subarachnoid needle placement, whereas localization of the epidural space must be inferred from the results of epidurograms and/or test doses of local anesthetic.

-

Subarachnoid neurolysis generally results in more profound analgesia than epidural neurolysis.

-

Subarachnoid injection is readily performed on an outpatient basis, or even at the bedside. Recent recommendations that epidural neurolysis be accomplished by repeated administration of phenol through an indwelling catheter mandates inpatient hospitalization.

-

Precise control over the block by proper positioning of the patient and minimizing the dose is possible with subarachnoid block as against the epidural block.

Sympathetic nerve blocks Neurolytic sympathetic blockade is useful to relieve pain in the arm, head and neck (stellate ganglion), or leg (lumbar sympathetic block), as well as to interrupt the visceral afferent pain pathways mediating pain in the pancreas and other upper abdominal organs (celiac block) or in the pelvis (hypogastric block). Local anesthetic infiltration of the sympathetic nervous outflow can be performed for diagnostic, prognostic, or therapeutic purposes. A diagnostic nerve block helps to establish the relative contribution of the autonomic vs. somatic nervous system to pain transmission. Finally, in carefully selected patients, a therapeutic effect may be obtained by the injection of a neurolytic agent. Neurolytic blocks are useful in the control of intractable visceral cancer pain. Neurolysis is typically achieved chemically using injections of alcohol (50% to 100%) or phenol (6% to 10%). Two neurolytic blocks commonly used to provide analgesia and aid in pain management are the celiac plexus block and superior hypogastric plexus block.94 When used with opioids,

385

neurolytic blocks allow opioid doses to be reduced, resulting in fewer side effects associated with opioids (eg, nausea/ vomiting, constipation, confusion, and sedation). Cervicothoracic sympathetic block or “Stellate ganglion block;” It is usually is performed by an experienced anesthesiologist for the indications such as postmastectomy pain syndrome, phantom limb pain and stump pain and Reflex sympathetic dystrophies in the upper limbs. Technique:-The patient is placed in supine position with the neck in slight extension. The operator then identifies the sixth cervical vertebral tubercle by locating the cricoid cartilage and moving the fingers laterally until they reach this easily palpable structure. The operator then places the index and third fingers between the carotid artery laterally and the trachea medially at the level of C6. A short 22 gauge needle is inserted until it contacts the transverse process of C6. The needle is then withdrawn approximately 1-2 mm and 5-10 ml of LA injected. Care must be taken to avoid intravascular injection or blockade of the recurrent laryngeal and phrenic nerves. Neurolytic Celiac plexus block (NCPB) Four-fifths or more of patients with pancreatic or other abdominal cancers derive pain relief from celiac block, usually lasting until death.95,96 Even when relief is incomplete, it may still lower the opioid dosage and thereby reduce drowsiness and constipation. It thus appears reasonable to consider early celiac neurolytic block for patients with a short life expectancy and pain from pancreatic cancer.96 Neurolytic celiac plexus block has received widespread attention because of its excellent potential to relieve upper abdominal and referred back pain secondary to malignant neoplasm involving upper abdominal structures like distal oesophagus, stomach, pancreas, gall bladder, bile ducts, liver, colon and duodenum Approaches :- (1)The posterior paravertebral percutaneous approach, introduced by Kappis, using two needles (12 in., 22 gauge) (2)Anterior approach with the help of interventional radiologists. (3) A transaortic technique, wherein the needle is deliberately passed through the aorta. (4) An underutilized approach is injection under direct vision by the surgeon at the time of laparotomy. Technique :- The location of the celiac axis is deep within the retroperitoneum near the vertebral column and in close proximity to major vessels (aorta, vena cava, and their branches) and viscera (kidneys, pleural). The L1 and T12 vertebral spines are identified and marked, and parallel lines to the vertical axis of the spine are drawn 7-8 cm from the axial midline. Then the border of the

386

PG ISSUE : PAIN

twelfth rib is palpated and marked. Connecting lines between these 3 marks produce a flat isosceles triangle. Skin wheals are placed over the marks immediately below the twelfth rib, and a 12-15 cm, 20-gauge needle (without the syringe) is inserted in a plane 45° to the horizontal. This placement allows contact with the L1 vertebral body at a depth of 6-8 cm. C-arm fluoroscopy is helpful for guiding the direction and depth of the needle. After this, the needle is withdrawn to subcutaneous level and reinserted at an angle to allow the tip to slip past the vertebral body. Aspiration after needle placement is critical prior to the injection of LA or a neurolytic agent. Besides blood, faulty needle puncture may yield urine or CSF. After this, 20-25 ml of 50% alcohol is injected on either side. Side effects of celiac block include pneumothorax, transient hypotension and diarrhea; Less likely complications are paraplegia or radicular weakness or numbness, intrarenal injection and damage, retroperitoneal hematoma, and failure of ejaculation.97,98 Lumbar sympathetic blockade Indications :- It is commonly indicated in the cases of Reflex sympathetic dystrophy, phantom limb and stump pain in lower limbs, Burger’s disease etc. Technique :- Ideally it should be performed with the help of C-arm. The patient is placed in prone position. The L3 and L4 vertebral spines are identified, and a mark is placed on the skin 6-8 cm lateral to the midline. A skin wheal is raised using a 15-cm, 22-gauge needle, which then is inserted through the skin at an angle of 30-45° from the vertical plane ascribed to the patient’s midline. The needle is advanced until it contacts the lateral aspects of the vertebral body. The needle may be redirected in a cephalad or caudal direction to avoid the transverse process. The target position for the needle is the anterolateral surface of the vertebral body. When the needle is in position, and after aspiration, 15-20 mL of LA solution, usually 0.5% lidocaine or 0.125-0.25% bupivacaine, is injected. Complications are rare but can occur, including accidental intravascular injection into the inferior vena cava or aorta, and unintentional needle penetration to neighboring somatic nerves Superior hypogastric plexus block and presacral neurectomy Superior hypogastric plexus block, a percutaneous procedure has recently emerged as an important option in the management of intractable pelvic pain of neoplastic origin, predominantly of gynaecological malignancies.


The superior hypogastric plexus, is a retroperitoneal structure located bilaterally at the level of lower third of the fifth lumbar vertebral body and upper third of the first sacral vertebral body at the sacral promontory and near the bifurcation of the common iliac vessels. It innervates following pelvic viscera: descending colon and rectum, vaginal fundus and bladder, uterus and ovary. This plexus block is usually performed under fluoroscopy and 6% aqueous Phenol is the neurolytic agent of choice. In a small study of 26 patients, the efficacy of superior hypogastric plexus block in reducing visceral pain associated with pelvic cancer was evaluated.99 All study participants had extensive gynecologic, colorectal, or genitourinary cancer and unremitting pelvic pain. After the block procedure, patients had significant reductions in their daily opioid intake. No complications from the procedure were reported. A cohort study of 227 patients with advanced pelvic cancer examined the efficacy and safety of superior hypogastric plexus block in reducing visceral pain associated with pelvic cancer.100 Patients enrolled in this study were taking oral opioids but experienced poor pain control. Patients had a significant amount of pain relief and significant reduction in their opioid intake. Ganglion of Impar block This procedure was recently proposed for sympathetically mediated pain involving the perineum and genitals, especially of a burning or urgent nature. Ganglion impar is a solitary retroperitoneal structure located at the level of the sacrococcygeal junction that marks the termination of the paired paravertebral sympathetic chains. In this, 0.2-0.5 ml of absolute alcohol or 6% aqueous phenol can be used. Good results and an absence of complications have been reported for perineal pain in patients with cancer of the cervix and cancer of endometrium. Common complications of chemical neurolysis Skin and other non-target tissue necrosis and sloughing: This is due to damage of the vascular supply to the skin, causing ischemia, and chronic trauma to denervated tissue. Neuritis : The reported incidence of neuritis is up to 10 percent. It is caused by partial destruction of somatic nerve and subsequent regeneration. Neuritis would occur only if the nerve cell body is not destroyed. It is less likely to occur with a subarachnoid or ganglion neurolytic block. It is clinically manifested as hyperesthesia and dysesthesia that may be worse than the original pain problem. Anesthesia Dolorosa : This is a poorly understood manifestation whereby the patient complains of distressing


numbness caused by an imbalance in afferent input. It is caused by long term loss of afferent input and the resultant CNS changes. Management of this problem is by use of different analgesics along with tricyclic antidepressants, major antipsychotic tranquilizers, and anticonvulsants. Prolonged motor paralysis : This can be a major complication and is greatly feared by physicians, patients and family. It occurs infrequently and is usually temporary. Perineal and sexual dysfunction : This is another fearsome complication that can occur temporarily. About 1.4 percent and 0.2 percent of patients will have bowel or bladder dysfunction at one week and one month, respectively. Systemic complications : These include hypotension secondary to sympathetic block and systemic toxic reactions, heart rate and rhythm disturbances, blood pressure changes, and CNS excitation and depression. Intrathecal pumps Only 2% to 5% cancer patients require interventions or the direct delivery of opioids to the central nervous system. Patients with unmanageable side effects may benefit from the epidural or intrathecal administration of opioids. Approximately one tenth of the intravenous dose of an opioid is needed when administered epidurally and one hundredth is needed when administered intrathecally. However, these procedures are expensive, and catheters and pumps are required to deliver the drug. To be cost effective, these devices should be used in a patient who has a life expectancy for longer than 3 months. Radiofrequency ablation This modality is becoming more popular in the present days. In this technique, the patient is sedated, an interventional radiologist uses a special needle to deliver radiofrequency current into the affected nerve, and destroys it. This procedure has fewer side effects and can provide pain relief for several weeks to months. It can also be repeated when necessary. It is used for ablation of intercostals nerves, trigeminal nerve, paravetebral nerves in the thorax and abdomen. Terminal stages : Palliative care In the terminally ill cancer patients, conventional pharmacotherapy and even invasive analgesic therapy may not provide adequate relief of pain. In the very terminal phase, procedural options should be used relatively sparingly. Options for the severe pain in this phase include subcutaneous infusions of opioids and/or sedatives. Haloperidol and corticosteroids can be helpful symptom control adjuncts in the terminal phase. Comprehensive palliative programs for end-of-life care may be considered

387

and can be inpatient or through home hospice. The physician should assess the needs of the patient and the family and fully discuss all care options. In addition to pain control, palliative care addresses the control of other symptoms associated with intractable cancer pain, including those relating to the physical, psychological, and religious or spiritual. Optimum quality of life is the primary goal of palliative care, which at the end of life is emotionally intense because of the multifactorial needs of the patient and family. Pain issue:- Surveys show that 55 percent of cancer patients experience disease-or treatment-related pain. Yet despite evidence of the effectiveness of the “analgesic ladder” promulgated by the World Health Organization (WHO), studies also show that pain is undertreated in as many as 46 percent of patients. The complexity and variability of pain as a symptom points to the need for a more selective and individualized therapy. Conclusions Cancer pain is very common and is often underestimated and undertreated. A successful management of pain is essential in the care of patients living with cancer or facing the end of life. -

Principles of pain management include a proper and regular assessment of pain, encouragement of patients and their families to use opioids for cancer pain, and aggressive management of side effects.

-

Pharmacotherapy continues to be the cornerstone of cancer pain management. A three-step analgesic “ladder” described by the WHO provides a general guideline for pain management. - -Opioids are the drugs of choice for moderate to severe cancer pain of all causes.

-

Usefulness and proper implementation of the interventional anesthetic and neurosurgical techniques is essential in the cancer patients with uncontrollable or refractory pain.

-

Nonpharmacological and complimentary therapies also should be used as and when needed.

-

Ultimate goal for the cancer pain management should be of ensuring a good quality of life and restoring physical and psychological health as far as possible.

References 1. Wingo PA, Cardinex CJ, Landis SH, Greenlee RT, Ries LA, Anderson RN. Long-term trends in cancer mortality in the United States, 1930–1998. Cancer.2003; 97(12 suppl): 3133 –1998. Erratum in Cancer 2005; 103(12): 2658.

388

PG ISSUE : PAIN

2. Fine PG. The evolving and important role of anesthesiology in palliative care. Anesth Analg 2005; 100: 183-188. 3 . Mercadante S, Fulfaro F. World Health Organization guidelines for cancer pain: a reappraisal. Ann Oncol 2005; 16(suppl 4): iv132-iv135. 4. Wootton M. Morphine is not the only analgesic in palliative care: literature review. J Adv Nurs.2004; 45: 527-532. 5 . Haegerstam GAT. Pathophysiology of bone pain: A review. Acta Orthop Scand 2001; 72: 308-317. 6. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. Pain 1999; 82: 263-274. 7. Manfredi PL, Gonzales GR, Sady R et al. Neuropathic pain in patients with cancer. J Palliat Care 2003; 19: 115-118. 8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003; 349: 1943-1953. 9. Silvestri GA, Sherman C, Williams T, Leong SS, Flume P, Turrisi A. Caring for the dying patient with lung cancer. Chest 2002; 122: 1028-1036. 10. Von Roenn JH, Cleeland CS, Gonin R et al. Physician attitudes and practice in cancer pain management: a survey from the Eastern Cooperative Oncology Group. Ann Intern Med 1993; 119(2): 121-26. 11. Houde RW. Methods for measuring clinical pain in humans. Acta Anaesthesiol Scand 1982; 74(suppl.): 25-29. 12. Sriwatanakul K, Kelvie W, Lasagna L. The quantification of pain: an analysis of words used to describe pain and analgesia in clinical trials. Clin Pharmacol Ther 1982; 32(2): 143-48. 13. World Health Organization. Cancer pain relief and palliative care. Report of a WHO expert committee [World Health Organization Technical Report Series, 804].Geneva, Switzerland: World Health Organization; 1990: 1-75. 14. Grond S, Zech D, Schug SA, Lynch J, Lehmann KA. Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991; 6(7): 411-22. 15. Weingart WA, Sorkness CA, Earhart RH. Analgesia with oral narcotics and added ibuprofen in cancer patients. Clin Pharm 1985; 4(1): 53-58. 16. Patrignani P, Tacconelli S, Scuilla MG, Capone ML. New insights into COX-2 biology and inhibition. Brain Res Brain Res Rev 2005; 48: 352-359. 17. McNicol E, Strassels S, Goudas L, Lau J, Carr D. Nonsteroidal anti-inflammatory drugs, alone or combined with opioids, for cancer pain: A systematic review. J Clin Oncol 2004; 22: 1975-1992. 18. Stockler M, Vardy J, Pillai A. Warr, D. Acetaminophen (paracetomal) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: A randomized, double-blind, placebo-controlled crossover trial. J Clin Oncol 2004; 22: 3389-3394. 19. Carr DB, Goudas LC, Balk EM, Bloch R, Ionnidis JP, Lau J. Evidence report on the treatment of pain in cancer patients. J Nat Cancer Inst Monogr 2004; 32: 23-31.

INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2006 20. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081-1091. 21. Wingo PA, Cardinex CJ, Landis SH, Greenlee RT, Ries LA, Anderson RN. Long-term trends in cancer mortality in the United States, 1930–1998. Cancer. 2003; 97(12 suppl): 3133 –1998. Erratum in Cancer. 2005; 103(12): 2658. 22. Mercadante S, Ferrera P, Villari P, Casuccio A. Rapid switching between transdermal fentanyl and methadone in cancer patients. J Clin Oncol 2005; 23: 5229-5234. 23. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetic. In: Miller RD, ed. Anesthesia. 5th Ed. Philadelphia, Pa: Churchill Livingstone 2000: 273-386. 24. Warren DE. Practical use of rectal medications in palliative care. J Pain Symptom Manage 1996; 11(6): 378-87. 25. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustainedrelease oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage 1997; 13(5): 254-61. 26. Payne R. Factors influencing quality of life in cancer patients: the role of transdermal fentanyl in the management of pain. Semin Oncol 1998; 25(3 Suppl 7): 47-53. 27. Cady J. Understanding opioid tolerance in cancer pain. Oncol Nurs Forum 2001; 28: 1561-1568 28. Parsons CG. NMDA receptors as targets for drug action in neuropathic pain. Eur J Pharmacol 2001; 429: 71-78. 29. Tarumi Y, Watanabe S, Bruera E et al. High-dose ketamine in the management of cancer-related neuropathic pain. J Pain Symptom Manage 2000; 19: 405-407. 30. Mercadante S, Arcuri E, Tirelli W et al. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, doubledose study. J Pain Symptom Manage 2000; 20: 246-252. 31. Jackson K, Ashby M, Martin P et al. “Burst” ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage 2001; 22: 834–842. 32. Kannan TR, Saxena A, Bhatnagar S et al. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage 2002; 23: 60-65. 33. Hocking G, Cousins M. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003; 97: 1108-1116. 34. Fine PG. The evolving and important role of anesthesiology in palliative care. Anesth Analg 2005; 100: 183-188. 35. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain management. Oncologist 2004; 9: 571-591. 36. Maizels M, McCarberg B. Antidepressants and antiepileptic drugs for chronic non-cancer pain. Am Fam Physician 2005; 71: 483-490. 37. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Ivengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005; 116(1–2): 109-18.


389

38. Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain 2000; 16(suppl 2): S67-S72.

55. Mercadante S, Fulfaro F, Casuccio A. The use of corticosteroids in home palliative care. Support Care Cancer 2001; 9: 386-389.

39. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs 2000; 60: 1029-1052.

56. Messer J, Reitman D, Sacks HS et al. Association of adrenocorticosteroid therapy and peptic-ulcer disease. N Engl J Med 1983; 309: 21-24.

40. Backonja MM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002; 59(suppl 2): S14-S17.

57. Byas-Smith MG, Max MB, Muir J et al. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain 1995; 60: 267-274.

41. Adriaensen H, Plaghki K, Mathieu C, Vissers K. Critical review of oral drug treatments for diabetic neuropathic pain— clinical outcomes based on efficacy and safety data from placebo-controlled and direct comparative studies. Diabetes Metab Res Rev 2005; 21(3): 231-240. 42. Morello CM, Leckband SG, Stoner CP et al. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999; 159: 1931-1937. 43. Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831-1836. 44. Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837-1842.

58. Eisenach JC, Du Pen S, Dubois M et al. Epidural clonidine analgesia for intractable cancer pain. Pain 1995; 61: 391-399. 59. Nadler SF, Malanga GA, Smith R et al. Open-label trial evaluating tizanidine for myofascial pain syndrome. Presented at the 10th World Congress on Pain, International Association for the Study of Pain 2002. 60. Vallejo R, Santigo-Palma J, Barna S et al. Tizanidine for the treatment of chronic myofascial pain. Presented at the 10th World Congress on Pain, International Association for the Study of Pain 2002. 61. Fulfaro F, Casuccio A, Ticozzi C et al. The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 1998; 78: 157-169.

45. Dallocchio C, Buffa C, Mazzarello P et al. Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study. J Pain Symptom Manage 2000; 20: 280-285.

62. Lipton A, Glover D, Harvey H et al. Pamidronate in the treatment of bone metastases: results of 2 dose-ranging trials in patients with breast or prostate cancer. Ann Oncol 1994; 5(suppl 7): S31-S35.

46. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain 2001; 94: 215-224.

63. Glover D, Lipton A, Keller A et al. Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study. Cancer 1994; 74: 2949-2955.

47. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 2003; 25: 81-104.

64. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7: 377-387.

48. Oneschuk D, al-Shahri MZ. The pattern of gabapentin use in a tertiary palliative care unit. J Palliat Care 2003; 19: 185-187. 49. Dworkin RH, Corbin AE, Young JP Jr et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebocontrolled trial. Neurology 2003; 60: 1274-1283. 50. Demoly P, Chung KF. Pharmacology of corticosteroids. Respir Med 1998; 92: 385-394. 51. Vecht CJ, Haaxma-Reiche H, van Putten WL et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 1989; 39: 1255-1257. 52. Ettinger AB, Portenoy RK. The use of corticosteroids in the treatment of symptoms associated with cancer. J Pain Symptom Manage 1988; 3: 99-103. 53. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 1994; 9: 442-45. 54. Farr WC. The use of corticosteroids for symptom management in terminally ill patients. Am J Hosp Care 1990; 7: 41-46.

65. Berenson JR, Rosen LS, Howell A et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91: 1191-1200. 66. Lipton A, Small E, Saad F et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002; 20(suppl 2): 45-54 67. Rosen LS. Efficacy and safety of zoledronic acid in the treatment of bone metastases associated with lung cancer and other solid tumors. Semin Oncol 2002; 29(suppl 21): 28-32. 68. Skerjanec A, Berenson J, Hsu C et al. The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function. J Clin Pharmacol 2003; 43: 154-162. 69. Roth A, Kolaric K. Analgesic activity of calcitonin in patient with painful osteolytic metastases of breast cancer: results of a controlled randomized study. Oncology 1986; 43: 283-287.

390

PG ISSUE : PAIN


70. Lewington VJ, McEwan AJ, Ackery DM et al. A prospective, randomised double-blind cross-over study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991; 27: 954-958.

86. Willick SE, Herring SA, Press JM. Basic concepts in biomechanics and musculoskeletal rehabilitation. In: Loeser JD, Bugler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 1815-1831.

71. Silberstein EB, Eugene L, Saenger SR. Painful osteoblastic metastases: the role of nuclear medicine. Oncology (Huntingt) 2001; 15: 157-163; discussion 167-170: 174.

87. Zaza C, Baine N. Cancer pain and psychosocial factors: a critical review of the literature. J Pain Symptom Manage.2002; 24: 526-542.

72. Lussier D, Portenoy RK. Adjuvant analgesics in pain management. In: Doyle D, Hanks G, Cherny N, et al., eds. Oxford Textbook of Palliative Medicine, 3rd ed. Oxford, England: Oxford University Press, 2003: 349-377.

88. Brietbart W, Payne D, Passik SD. Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks NC, Calman K, eds. Oxford Textbook of Palliative Medicine. 3rd ed. New York, NY: Oxford University Press; 2004: 424-438.

73. Bruera E, Ripamonti C, Brenneis C et al. A randomized double-blind crossover trial of intravenous lidocaine in the treatment of neuropathic cancer pain. J Pain Symptom Manage 1992; 7: 138-140.

89. Monti DA, Yang J. Complementary medicine in chronic cancer care. Semin Oncol 2005; 225-231.

74. Campbell RW. Mexiletine. New Engl J Med 1987; 316: 29-34.

90. Genuis ML. The use of hypnosis in helping cancer patients control anxiety, pain, and emesis: a review of empirical studies. Am J Clin Hypn 1995; 37: 316-325.

75. Galer BS, Rowbotham MC, Perander J et al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999; 80: 533-538.

91. Alimi D, Rubino C, Pichard-Leandri E, Fermand-Brule S, Dubreuil-Lemaire ML, Hill C. Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial. Clin Oncol 2003; 21: 4120-4126.

76. Gammaitoni AR, Davis MW. Pharmacokinetics and tolerability of lidocaine patch 5% with extended dosing. Ann Pharmacother 2002; 36: 236-240.

92. Rodriguez-Bigas M, Petrelli NJ, Herrera L, West C. Intrathecal phenol rhizotomy for management of pain in recurrent unresectable carcinoma of the rectum. Surg Gynecol Obstet 1991; 173(1): 41-44.

77. Ellison N, Loprinzi CL, Kugler J et al. Phase III placebocontrolled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997; 15: 2974-2980. 78. Fromm GH. Baclofen as an adjuvant analgesic. J Pain Symptom Manage 1994; 9: 500-09.

93. Salmon JB, Finch PM, Lovegrove FT, Warwick A. Mapping of spread of epidural phenol in cancer pain patients by radionuclide admixture & epidural scintigraphy. Clin J Pain 1992; 8: 18-22.

79. Reddy S, Patt RB. The benzodiazepines as adjuvant analgesics. J Pain Symptom Manage 1994; 9: 510-514

94. De Leon-Casasola OA. Critical evaluation of chemical neurolysis of the sympathetic axis for cancer pain. Cancer Control 2000; 7: 142-148.

80. Dalal S, Melzack R. Potentiation of opioid analgesia by psychostimulant drugs: a review. J Pain Symptom Manage 1998; 16: 245-253.

95. Brown DL, Bulley CK, Quiel EL. Neurolytic celiac plexus block for pancreatic cancer pain. Anesth Analg 1987; 66(9): 869-73.

81. Rozans M, Dreisbach A, Lertora JJ et al. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol 2002; 20: 335-339.

96. Mercadante S. Celiac plexus block versus analgesics in pancreatic cancer pain. Pain 1993; 52: 187-92.

82. Raj PP. Botulinum toxin therapy in pain management. Anesthesiol Clin North America 2003; 21: 715-731. 83. Van Daele DJ, Finnegan EM, Rodnitzky RL et al. Head and neck muscle spasm after radiotherapy: management with botulinum toxin A injection. Arch Otolaryngol Head Neck Surg 2002; 128: 956-959. 84. Mystakidou K, Tsilika E, Kalaidopoulou O et al. Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blind, controlled clinical trial. Anticancer Res 2002; 22: 1187-1192. 85. Sutton LM, Porter LS, Keefe FJ. Cancer pain at the end of life: a biopsychosocial perspective. Pain 2002; 99: 5-10.

97. Ischia S, Ischia A, Polati E, Finco G. Three posterior percutaneous celiac plexus block techniques. A prospective, randomized study in 61 patients with pancreatic cancer pain. Anesthesiology 1992; 76(4): 534-40. 98. van Dongen RT, Crul BJ. Paraplegia following coeliac plexus block. Anaesthesia 1991; 46(10): 862-63. 99. De Leon-Casasola OA, Kent E, Lema MJ. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer pain. Pain 1993; 54: 145-151. 100. Plancarte R, de Leon-Casasola OA, El-Helay M et al. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Reg Anesth. 1997; 22: 562-568.