Pain control in Cancer patients. Dr Ali Shoeibi, Assistant Professor of Neurology

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2 Pain control in Cancer patients Dr Ali Shoeibi, Assistant Professor of Neurology

3 More than two thirds of patients with advanced cancer experience cancer pain Almost all pain can be controlled to some extent with the wide range of available treatments Pain can be classified in nature as: Nociceptive Somatic Visceral Neuropathic

4 Physiological effects of Pain Increased catabolic demands: poor wound healing, weakness, muscle breakdown Decreased limb movement: increased risk of DVT/PE Respiratory effects: shallow breathing, tachypnea, cough suppression increasing risk of pneumonia and atelectasis Increased sodium and water retention (renal) Decreased gastrointestinal mobility Tachycardia and elevated blood pressure

5 Psychological effects of Pain Negative emotions: anxiety, depression Sleep deprivation Existential suffering

6 Immunological effects of Pain Decrease natural killer cell counts Effects on other lymphocytes not yet defined

7 Key principles of the WHO method of cancer pain relief 1. Cancer pain can, and should, be treated 2. Evaluation and treatment of cancer pain are best achieved by a team approach

8 Key principles of the WHO method of cancer pain relief 3. The first steps are to take a detailed history, and to examine the patient carefully, to determine if the pain is: caused by the cancer, related to the cancer, caused by anticancer treatment, or caused by another disorder; part of a specific syndrome; nociceptive, neuropathic, or mixed nociceptive and neuropathic 4. Treatment begins with an explanation and combines physical and psychological approaches, using both nondrug and drug treatments

9 Key principles of the WHO method of cancer pain relief 5. It is useful to have a sequence of specific aims, such as to: 1. increase the hours of pain-free sleep; 2. relieve the pain when the patient is at rest; 3. relieve pain when the patient is standing or active 6. Drugs alone usually give adequate relief from pain caused by cancer, provided that the right drug is administered in the right dose at the right time intervals 7. By mouth : the oral route is the preferred route for analgesics, including morphine

10 Key principles of the WHO method of cancer pain relief 8. By the clock : for persistent pain, drugs should be taken at regular time intervals and not as needed 9. By the ladder : Unless the patient is in severe pain, begin by prescribing a nonopioid drug and adjust the dose, if necessary, to the maximum recommended dose If or when the nonopioid no longer adequately relieves the pain, an opioid drug should be prescribed in addition to the nonopioid If or when the nonopioid for mild to moderate pain (e.g. codeine) no longer adequately relieves the pain, it should be replaced by an opioid for moderate to severe pain (e.g. morphine)

11 Key principles of the WHO method of cancer pain relief 10. For the individual : the right dose of an analgesic is the dose that relieves the pain. The dose of oral morphine may range from as little as 5 mg to more than 1000mg 11. Adjuvant drugs should be prescribed as indicated. For neuropathic pain, a tricyclic antidepressant or an anticonvulsant is the analgesic of choice 12. Attention to detail : it is essential to monitor the patient s response to the treatment to ensure that the patient obtains maximum benefit with as few adverse effects as possible

12 By the mouth the oral route The oral route of analgesic therapy is preferred as: 1. it is simple, acceptable, and relatively cheap 2. Most analgesics, including opioids, have clinically useful oral bioavailability 3. Oral therapy requires little medical intervention and therefore the patient is independent of infrastructure and personnel 4. The delayed absorption after oral administration prolongs the duration of action of most drugs Disadvantages: 1. in the setting of acute (e.g. Incident pain) the later peak time with oral administration may convey disadvantages 2. It may not be the preferred rout in the setting of: vomiting impaired swallow gastrointestinal obstruction malabsorption coma

13 OTHER ROUTES OF DRUG Transdermal: ADMINISTRATION avoids the problem of first pass metabolism Lipid soluble, low molecular weight drugs are more appropriate for this route Absorption is slow, and therapeutic levels can be maintained for many days Compliance is usually good Fentanyl and buprenorphine are available in patch form for transdermal administration

14 OTHER ROUTES OF DRUG ADMINISTRATION The rectal route Advantages: is cheap and requires no specialized skills The rectal veins drain to both the hepatic portal vein and the inferior vena cava, thus some first pass metabolism is avoided analgesia is of more rapid onset and longer duration than that achieved via the oral route Morphine is well absorbed rectally Disadvantages: absorption is often variable Local irritation can occur the variability of drainage makes uptake unpredictable should not be used in patients with diarrhea or fecal incontinence Immunosuppressed patients are at risk of localized infection Administration of opioids via colostomy has been shown not to be useful, probably due to comparatively poor vascularity

15 OTHER ROUTES OF DRUG ADMINISTRATION Parenteral administration Changing from enteral to parenteral administration requires adjustment, usually reduction of dose and frequent reassessment to take into account bioavailability differences resulting from lack of first-pass effect with the parenteral route Subcutaneous bioavailability may be more than 90 percent for most drugs, but depends on: The solubility of the drug, cardiovascular conditions, peripheral perfusion, the injection site, and physical exercise The availability of simple portable syringe pumps has made continuous subcutaneous morphine administration easy and acceptable for the patient who is unable to take oral medication is relatively cheap, requiring little medical input for administration Intramuscular administration is not generally recommended

16 By the clock regular around the clock medication Chronic pain, as occurs in patients with cancer, requires preventative therapy on a regular basis, thus: Avoiding recurrences of pain with unnecessary suffering Avoiding the potential development of chronic pain behavior The dose intervals should be guided by the pharmacokinetics of the drugs utilized, with each successive dose given before the preceding one has worn off Slow or sustained release preparations should be prescribed whenever available, as their use extends dosing intervals and stabilizes plasma concentrations Patients should also be provided with analgesic therapy to use as required or PRN for breakthrough or incident pain. This is also referred to as rescue analgesia

17 By the ladder sequential use of analgesic medication Analgesics are selected according to increasing pain intensity in a sequential approach Inadequate pain relief at one level results in a step up to the next level instead of changing to another drug on the same level In parallel, it encourages the combined use of nonopioid and opioid analgesics with adjuvant or coanalgesic drugs

18 STEP ONE: USE OF NONOPIOIDS For control of pain of mild to moderate intensity Examples within this group include: Paracetamol, dipyrone, traditional nonsteroidal antiinflammatory drugs (NSAID), and the newer COX-2 inhibitors In contrast to opioids, nonopioids do show a ceiling effect to their analgesic action Inadequate pain control by their use at maximum doses makes a move up the ladder necessary, if appropriate adjuvant therapy is already being used and cannot be improved

19 The benefits gained from the first step should be continued, however, even as stronger analgesia is required The combination of NSAIDs and a strong opioid, has been demonstrated to: enhance analgesia and patient satisfaction decrease opioid use without an increase in side effects

20 STEP TWO: USE OF WEAK OPIOIDS the addition of a weak opioid without discontinuation of the nonopioid Examples of drugs within this category include: Codeine phosphate, dextropropoxyphene, dihydrocodeine, and tramadol This second step is currently the subject of a wide-ranging discussion with its use being questioned in terms of: Its pharmacological validity (e.g. low doses of a strong opioid given as an alternative in step two) Its efficacy Tramadol is listed as a step two opioid, although it is better described as an atypical centrally acting analgesic because its mechanism of action combines opioid and monaminergic properties It is effective in both nociceptive and neuropathic pain

21 STEP THREE: USE OF STRONG OPIOIDS When the first two steps fail, a weak opioid is replaced with a strong opioid, again without abandoning the nonopioids and adjuvants a strong opioid should be immediately started in the setting of initial presentation with severe cancer pain Further increases in pain are then counteracted with increasing doses of strong opioid Morphine is the gold standard strong opioid of choice as recommended by the WHO

22 acceptable analgesia can be achieved in over 80 percent by using morphine in combination with a nonopioid analgesic Morphine has no clinically significant ceiling effect to analgesia, allowing large variation in the doses used to achieve pain relief limitations to morphine therapy: the accumulation of active metabolites in renal impairment lack of complete response in some pain types (particularly neuropathic pain) Large interindividual variability in morphine pharmacokinetics requiring careful titration against pain relief

23 other strong oral opioids include: Methadone, oxycodone, and hydromorphone Fentanyl and buprenorphine are also available in sustained release topical delivery systems (patches) Due to accumulation of neurotoxic metabolites, particularly in renal impairment, and its short duration of action, pethidine is not recommended

24 Fears of side effects such as respiratory depression, tolerance, and physical dependence and psychological dependence have led to worldwide underutilization of step 3 Pain acts as a stimulant to counteract any initial respiratory centre depression, while the CNS rapidly becomes tolerant to the depressant effects of opioids over time Therefore, respiratory depression due to opioid treatment of cancer pain almost never occurs the sudden relief of pain by other procedures (e.g. Neurolysis) or spinal cord compression when high doses of opioids, suddenly not counterbalanced by pain, can lead to respiratory depression

25 Because of the common occurrence of nausea and constipation with the use of strong opioids it is advisable to initiate therapy in combination with a regular antiemetic and laxative Nausea often subsides as treatment continues over a few weeks, but treatment for constipation needs to be both continued and aggressive Sedation also will usually subside within a week of stable dosing If sedation or nausea is persistent, rotating to another opioid may be useful, as cross-tolerance between strong opioids is often incomplete Cognitive impairment lasts no longer than a week and patients on stable doses of opioid have no gross change in cognitive abilities Other less frequent side effects of strong opioids are pruritus, urinary retention, and sweating

26 USE OF ADJUVANTS At any step, additional adjuvants and coanalgesic drugs should be added as appropriate for the individual patient Examples of coanalgesic drugs used here include: medications for the treatment of neuropathic pain Bisphosphonates Steroids Many other groups of drugs may be used to treat the adverse effects of analgesics, to enhance pain relief and to treat concomitant psychological disturbances such as insomnia, anxiety, and depression

27 Adjuvants Antidepressants TCAs for neuropathic pain Anticonvulsants Corticosteroids Neuroleptics Alpha 2 agonists Benzodiazepines Antispasmodics Muscle relaxants Systemic/local anesthetics

28 Adjuvants Bone pain Bisphosphonates Calcitonin Pain from malignant bowel obstruction Steroids Octreotide Anticholinergics Practice Points: Choose adjuvant carefully (risk:benefit) Start low and titrate gradually Avoid initiating several adjuvants concurrently

29 Adjuvant Analgesics for neuropathic pain CLASS EXAMPLES Anticonvulsants Antidepressants Local Anesthetics gabapentin, valproate, phenytoin, carbamazepine, clonazepam, topiramate, lamotrigine amitriptyline, desipramine, nortriptyline, paroxetine, citalopram, others mexiletine Corticosteroids dexamethasone, prednisone α-2 Adrenergic Agonists tizanidine NMDA-Receptor Agonists dextromethorphan, ketamine Topicals lidocaine, lidocaine/prilocaine, capsaicin Miscellaneous baclofen, calcitonin

30 Point It is recommended that only one agent from each group be used at one time When one drug fails to provide pain relief, a representative of the next step should be used rather than switching within a group of drugs with similar efficacy and potency However, if one drug results in unacceptable side effects, then it should be replaced by another agent from the same step

31 RESCUE ANALGESICS A short-acting opioid, such as immediate-release morphine, should be available to all cancer patients taking controlled-release preparations to treat pain not covered by their regular medications This is referred to as breakthrough pain or Incident pain Reassessment of the pain and increased doses of controlled release preparation, guided by the amount of rescue analgesia used, will usually be required

32 For the individual Setting realistic and obtainable aims of analgesic therapy clarifies the titration process Aiming for a goal that is too high initially can result in early failure, thereby frustrating the patient and possibly undermining trust in the treating physician In general, titration should be performed only with immediate-release and not with controlled-release preparations

33 Point if a starting opioid dose provides good analgesia, but with excessive sedation, then the subsequent dose should be 50 percent lower If, on the initial dose, pain relief is inadequate after 24 hours, then doses should be increased, based on rescue drug used, but a typical increase would be by 50 percent, with frequent reevaluation at least at 48 and 72 hours

34 Other Interventions Interventional therapies should be considered concurrently with the use of the ladder. It is therefore not appropriate to regard interventional techniques as a final fourth step of the ladder??????? In carefully selected patients with: 1. intractable pain unresponsive to adequately dosed opioids and other therapies 2. With intolerable adverse effects 3. with adequate prognosis use of intraspinal analgesia, particularly involving the use of nonopioids (eg, clonidine) neurolytic celiac plexus block for pancreatic cancer Palliative surgery/kyphoplasty/vertebroplasty

35 Nociceptive Somatic Results from inflammation and stimulation of nociceptors Tumor / Mass effect/musculoskeletal sharp, localized Visceral Is encountered in patients with primary or metastatic tumor infiltration into the viscera, such as the pancreas, liver, gastrointestinal tract, and lung is diffuse and poorly localized, and the pain is often referred to distant, and often superficial, somatic structures Autonomic reflexes, such as nausea and vomiting, may accompany visceral pain

36 Neuropathic Pain at least percent of patients are likely to suffer from neuropathic pain during the course of the disease neuropathic pain presents with complex multiple symptoms which include a combination of positive and negative signs, such as: sensory loss (numbness), spontaneous pain, allodynia, hyperalgesia, and paresthesia Mechanism: compressing or infiltrating nerves/nerve roots/blood supply to nerve Nerve damage from treatments Shooting, sharp, burning, pins & needles Examples: Cranial neuropathies/post-herpetic neuropathies Brachial plexus neuropathies/post-radiation

37 Neuropathic Pain Chemotherapy-induced neuropathies Cisplatin, Oxaliplatin Paclitaxil, Thalidomide Vincristine, Vinblastine Surgical Neuropathies Phantom limb pain Post-mastectomy syndrome Post-thoracotomy syndrome

38 Multiple Pain Mechanisms 1. Nociception 2. Peripheral sensitization 3. Central sensitization 4. Decreased inhibition/structural reorganization

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40 Nociception Transduction Conduction Transmission Noxious stimulus Modulation primary sensory neuron central neuron

41 Peripheral Sensitization Reduced Transduction Threshold Innocuous/Noxious stimulus Primary hyperalgesia Primary allodynia Inflammation primary sensory neuron central neuron

42 Central Sensitization Increased Pain Responsiveness Noxious stimulus Secondary hyperalgesia and allodynia Irritants Tissue damage Inflammation primary sensory neuron central neuron

43 Pain Intensity Rating Scales Visual Analogue Scale (VAS) No pain Worst pain Numerical Rating Scale No pain Categorical Scale None (0) Mild (1 4) Moderate (5 6) Severe (7 10) 10 Worst pain imaginable

44 Pain Intensity Rating Scales Pain Faces Scale No hurt Hurts just a little bit Hurts a little bit more Hurts even more Hurts a whole lot Hurts as much as you can imagine

45 Quantifying pain In a patient with advanced or terminal illness, asking the patient and believing his/her report is the most appropriate approach for screening for pain (VAS) In a patient with advanced illness, the provider should evaluate for signs of potential pain such as grimacing with touch or movement, moaning, or withdrawing especially with interventions such as turning If an advanced cancer patient has a clear reason for pain or is receiving treatments that would be painful in a conscious individual, providers should treat the patient for pain even if he/she cannot verbalize discomfort

46 Assessment should include evaluating for medical or oncological emergencies Treatable syndromes, including fractures, infections, and obstruction 17% of patients pain is due to adverse effects of cancer treatment, and the burdens and benefits of such treatments should be reconsidered A complete whole patient evaluation also includes assessment for other symptoms and sources of suffering, particularly depression, and stress or family conflict related to the pain