Cancer%20pain Treatment

• Symptom control and support should be prioritized when dealing with cancer pain-
  • Studies revealed that symptom control improves survival rates and quality of life
• Goals of pain control involves optimizing the “5As”: Analgesia, activities, adverse effects, aberrant drug intake and affect
  • Analgesic treatments should be utilized at its maximum potential
  • Return to routine activities must be achieved
  • Adverse effects of treatments should be kept to a minimum
  • Drug intake should be monitored to avoid aberrant drug taking
  • Pain should not affect patient's mood
• Shifting from high-dose non-opioid analgesics, to non-opioid-opioid combination, to pure opioid preparations are recommended for more effective control of pain to avoid the toxicities of non-opioid agents
• Opioid rotation should be considered if pain is inadequately controlled, dose-limiting adverse effects are present, and further titration is not possible
• Regular intake of pain medication, with supplemental doses for breakthrough pain, is the preferred strategy for continuous pain
• Addition of extended-release or long-acting formulations to short-acting opioids are recommended for effective control of chronic persistent pain 
• Pharmacological cancer pain treatment generally have an oral route of administration and dose of analgesic have an “around the clock” regimen
• Other routes of administration can be considered eg intravenous (IV), subcutaneous (SC), rectal, transdermal, transmucosal in order that the patient have pain relief and comfort
• Analgesic regimen is based on pain severity that starts with non-opioid analgesics for mild pain, mild opioid analgesics for moderate pain, and progress to strong opioids for severe pain

Non-Opioid Analgesics

• Eg Paracetamol (Acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDs), Ketamine, Lidocaine (IV)
• Indicated for treatment of mild to moderate pain
• Lowest effective dose is recommended in shortest period to control symptoms in order to prevent potential side effects [eg hepatotoxicity, gastrointestinal (GI) bleeding, renal failure and thrombotic cardiovascular events]
• May shift to another NSAID if treatment is limited by toxicities, or may consider other agents if pain relief is inadequate despite use of 2 successive NSAIDs
• Topical NSAID may be considered if oral administration is not feasible 
• COX-2 inhibitors may be considered for patients with history of gastrointestinal or hematologic diseases
• Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, may help provide analgesia and modulate central sensitization, hyperalgesia and opioid tolerance in opioid-resistant cancer pain
• IV Lidocaine infusion is given in patients with refractory cancer pain
• When used with opioid analgesics, it may produce better pain relief and lower incidence of opioid-related side effects

Opioid Analgesics

• Mainstay of analgesic therapy and may be combined with non-opioid drugs such as Paracetamol or nonsteroidal anti-inflammatory drugs and with adjuvant drugs
• Should be considered for cancer survivors with chronic pain who are unresponsive to non-opioid analgesics and other conservative therapies
• Weak opioids (eg Tramadol, Dihydrocodeine, Codeine) are indicated for mild to moderate cancer pain
• Strong opioids/pure agonists (eg Morphine, Oxycodone, Oxymorphone, Fentanyl) are the most commonly used opioids in the management of moderate to severe cancer pain
• Opioid-naive patients are those who have no history of opioid intake while opioid-tolerant patients are the ones who have previously or have chronically taken opioids on a daily basis for cancer pain relief
• For opioid-naive patients that are experiencing moderate pain, slow titration of short-acting opioids (Morphine, Hydromorphone, Fentanyl, Oxycodone) is suggested
• Opioid-naive patients experiencing severe pain should receive rapid titration of short-acting opioids
  • Short-acting formulations have the advantage of rapid onset of analgesic effect
  • Route of administration depends on what is best suited to the patient’s ongoing analgesic needs
• Should be used with caution in patients with fluctuating renal function due to potential accumulation of renally cleared metabolites especially in patients prescribed with Codeine, Morphine, Hydromorphone, Hydrocodone, and Oxymorphone
• Opioid allergy especially in patients experiencing pruritus should prompt reconsideration of opioid therapy

Buprenorphine

• A partial mu-receptor antagonist that has been approved for chronic pain in patients who are opioid naive or opioid tolerant
• Treatment option for patients with renal impairment
• Transdermal Buprenorphine is a treatment option for opioid-naive patients that need initiation of long-acting opioid therapy; buccal Buprenorphine may also be used if needed

Codeine

• A weak mu- and delta-opioid receptor agonist
• Provides little or no direct analgesia especially in patients who are poor metabolizers

Fentanyl

• A semisynthetic mu-opioid receptor agonist with high lipid solubility
• For patients whose opioid requirements are stable, who are unable to swallow, cannot tolerate Morphine or with poor compliance
• Transdermal Fentanyl should only be considered for patients whose pain has previously been managed and was responsive to other opioids, and is not indicated for rapid opioid titration
• Transmucosal Fentanyl formulations (oral, buccal, sublingual, and intranasal) are effective options for managing cancer patients with unpredictable and rapid-onset breakthrough pain
  • It is applicable in patients receiving doses of oral Morphine equivalents of at least 60 mg
  • May be considered in patients who are opioid-tolerant for brief episodes of incident pain not attributed to inadequate dosing of an around-the-clock opioid

Hydrocodone

• A mu- and delta-opioid receptor agonist used as a mild, initial-use opioid,with varied effective dose
• Only available in combination with oral agents such as Ibuprofen and Paracetamol

Hydromorphone

• A mu-opioid receptor agonist and weak delta-opioid receptor agonist with properties identical to Morphine
• Studies have shown that Hydromorphone can effectively reduce moderate to severe pain in cancer patients previously unresponsive to other analgesics but may be more neurotoxic compared to Morphine

Levorphanol

• A mu-/delta-/kappa-opioid receptor and NMDA receptor antagonist with shorter half-life compared to Methadone
• Efficacy is comparable to Methadone but with lesser adverse effects

Methadone

• A mu receptor and NMDA receptor antagonist used as an option for the treatment of chronic cancer-related pain
• Should be given at lowest dose (50%) during initiation and slowly titrated upwards to prevent adverse effects secondary to its long half-life, high potency, and variations in pharmacokinetics per individual
• It should be used only as prescribed by a pain specialist of palliative care
• Alternative option for patients experiencing hyperalgesia or unrelieved pain even with concurrent opioid use and those with indications for opioid rotation
• Can be considered in patients who can only tolerate a long-acting opioid analgesic in crushed or liquid form
• Addition of a short-acting opioid to Methadone therapy should be provided for breakthrough pain

• A mu-opioid receptor agonist and weak kappa receptor agonist
• Standard starting treatment in opioid-naive patients who has moderate to severe cancer pain
• Oral administration is the preferred route for opioid-naive patients while intravenous (IV) or subcutaneous (SC) route is preferred for patients with severe pain that needs urgent relief

Oxycodone

• Used as an alternative strong opioid with agonist activity at the mu-, delta-, and kappa-opioid receptors
• Analgesic and adverse effects are comparable to that of Morphine for the treatment of cancer-related pain
• Studies have shown that combination with Naloxone produces analgesia with reduced constipation compared to opioid monotherapy

Oxymorphone

• A long-acting mu-opioid receptor agonist
• Should be used with caution in patients with renal dysfunction

Remifentanil

• An opiate agonist with analgesic effects
• May be used in pain management of intensive care and postoperative patients
• Further investigations are needed to asses the suitability of Remifentanil for use in cancer pain and renal impairment

Dual Mechanism Opioids

• Eg Tramadol, Tapentadol
• Acts on both opioid receptors and neurotransmitter reuptake inhibitor
• Tapentadol is a μ-opioid receptor and norepinephrine reuptake inhibitor used for moderate to severe pain as well as for neuropathic pain
• Tramadol, a weak mu-opioid agonist with modest norepinephrine and serotonin reuptake inhibitor properties, may be used for mild to moderately severe pain
  • Considered to be less potent compared to other opioids
• Tapentadol and Tramadol should be used with caution or not at all in patients receiving tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), or serotonin and noradrenaline reuptake inhibitors (SNRIs) due to potential risk of serotonin syndrome

Adjuvant Therapy

• Medications that are coadministered to manage an adverse effect of an opioid or to adjuvant analgesics that are added to enhance analgesia

Analgesics

• Also called co-analgesics; may be used alone or in combination with other analgesics including strong opioids
• Usually used in treatment of bone pain, neuropathic pain, visceral pain

Antidepressants

• Eg TCAs (eg Amitriptyline, Desipramine, Imipramine, Nortriptyline), SNRIs (eg Duloxetine, Venlafaxine)
• First-line adjuvant analgesic used in the treatment of cancer-related neuropathic pain
• Used in combination with opioids for relief of the neuropathic component of cancer pain

Anticonvulsants

• Eg Gabapentin, Pregabalin
• First-line adjuvant analgesic used in the treatment of neuropathic pain, mucositis pain in patients receiving concomitant radiotherapy and chemotherapy
• Used in combination with opioids for relief of the neuropathic component of cancer pain

Anxiolytics

• Eg Alprazolam, Diazepam, Lorazepam, Midazolam
• Used for the treatment of anxiety and related psychologic and physical symptoms
• Should be given preemptively to patients scheduled to undergo procedures that are frequently accompanied by pain and anxiety

Corticosteroids

• Eg Dexamethasone 
• Have been used in relief of neuropathic pain from spinal cord compression, bone pain, headache from brain metastases, abdominal pain from liver capsule distension or intestinal obstruction
• Not recommended as long-term treatment if to be used only for pain relief

• Eg 5% Lidocaine patch, topical NSAIDs
• Exerts its effects locally and usually given in combination with opioids, antidepressants, and/or anticonvulsants
• May be considered for neuropathic pain

Investigational Agents

• Nabiximol, a Cannabis sativa extract that contains the cannabinoids D9-tetrahydrocannabinol and cannabidiol, is being studied as an adjunctive therapy for patients whose cancer pain is not completely controlled by opioids

Opioid Switching (Rotation)

• Treatment strategy which involves changing of an opioid with an equivalent dose of an alternative opioid to enhance the balance between the analgesic therapy and its side effects
• It is indicated in patients with:
  • Inadequate pain relief despite appropriate dose titration of the initial opioid
  • Intolerable side effects (eg sedation, nausea, vomiting, constipation)
  • Renal impairment
  • Practical considerations (eg patient preference, inability to swallow, etc)
• Opioids that can be used for switching are Oxycodone, Fentanyl and Methadone
• Equianalgesic conversion tables should be the guide in changing one opioid to another or between different routes of administration

Other Supportive Agents

• Naloxone should be prescribed and caregiver should be educated on the proper administration and usage in the event of respiratory depression and sedation
• Bisphosphonates and Denosumab may be used for painful metastatic disease to help inhibit osteoclast-mediated bone resorption, potentially reducing the risk of bone fracture and related bone pain

Psychosocial Support

• Cancer pain management goals include the patient’s comfort, function and safety
• Cognitive behavioral interventions and psychosocial support can help in alleviating the patient’s pain severity but also the psychological distress related to it
• Cognitive interventions aim to enhance the sense of control over the pain or underlying disease

Physical and Complementary Therapy

• Physical modalities such as bed/bath/walking supports, positioning instruction, therapeutic or conditioning exercise (eg breathing exercises), massage, heat and/or ice, acupuncture/acupressure, transcutaneous electrical nerve stimulation (TENS), and ultrasonic stimulation can help reduce pain in some cancer patients
  • Massage with or without aromatherapies can give transient relief of pain as well as other cancer-related symptoms
  • It was found that acupuncture can be effective in relieving chronic neuropathic cancer pain
• Cognitive modalities such as distraction techniques, relaxation techniques, mindfulness-based stress reduction (MBSR), hypnosis, biofeedback, guided imagery, acceptance-based training, active coping training, graded task assignments, hypnosis to maximize function, cognitive behavioral therapy (CBT), cognitive restructuring and behavioral activation may be considered

Interventional Techniques

• Indicated in patients who have significant pain from locally advanced disease, severe neuropathic pain and severe pain on movement, those who are likely to respond to nerve block, and with intolerable side effects despite adequate analgesic treatments
• Neurolytic sympathetic plexus blocks (ie neurolytic celiac plexus block, splanchnic nerve block, neurolytic superior hypogastric plexus block) involves instilling alcohol or phenol with local anesthetics into the nerve plexus that can ablate the sympathetic nerve supply to painful viscera
  • It can be considered in patients with pain from pancreatic cancer
• Neuraxial opioid therapy (epidural and intrathecal opioids) with or without anesthetics can be used in diffuse pain from advanced cancer
• For bone lesions causing severe pain, may use percutaneous vertebral augmentation and/or cementoplasty
  
  • Vertebroplasty and kyphoplasty involves the introduction of bone cement directly into cancellous bone of the vertebral body to relieve pain due to spinal metastases, vertebral compression fractures, or spinal instability
  • Kyphoplasty utilizes an intervertebral balloon prior to bone cement injection
  • It can be considered in patients with uncontrolled bone pain from malignant vertebral collapses
• Orthopedic interventions (eg internal fixation of pathological long bone fractures) can be considered in patients whose life expectancy is more than 4 weeks or who are fit to undergo the procedure to relieve pain
• Ablative surgery to remove large tumors can improve pain control in some painful fungating breast lesions or large sarcomas if pharmacological intervention did not give optimal pain relief
• Percutaneous ablation techniques may also be considered for painful bone lesions
• Pain due to malignant bowel obstruction may be relieved by palliative surgical procedures ie colostomy or bypass procedures
• External beam radiotherapy has been found to be effective in the management of metastatic bone pain and in metastatic spinal cord compression (mSCC)
• May consider radiopharmaceutical therapy [eg Samarium-153 (153Sm), Strontium-89 (89Sr), Radium-223(223-Ra)] in patients who have failed traditional radiotherapy or those with polymetastatic disease who are not candidates for palliative radiation
• Neurostimulation procedures for patients with cancer-related symptoms and neurodestructive procedures for pain syndromes which are well localized