Cancer Pain

Dr. Akshay Goyal

Transcript

1. PAIN MANAGEMENT IN CANCER PATIENTS RUTGERS RWJUH DEPARTMENT OF ANESTHESIOLOGY AND PAIN MEDICINE MAY 11, 2022
2. OBJECTIVES  Discuss epidemiology of cancer pain  Review pathophysiology of cancer pain  Discuss pharmacologic treatment options, including anti-inflammatories, anticonvulsants, antidepressants  Discuss intrathecal delivery system  Discuss neurolysis for cancer pain, including alcohol and phenol  Discuss neurosurgical options for cancer pain
3. Epidemiology of Cancer Pain  Average age at cancer diagnosis is 65  60-90% of pts will have pain  Pain from disease or treatment?  In pediatrics, it is more commonly from treatment  Pain as first sx of cancer tends to indicate advanced disease and is an independent predictor of poor prognosis
4. Special Populations  In pediatrics, pain is more commonly from treatment  In geriatric population, comorbidities and drug-drug interactions need to be taken into effect  In patients with substance abuse history, there is greater reliance on diagnostic imaging  Inmates have higher rates of cancer, increased mortality, and undertreated symptoms
5. Sources of pain  Direct tumor invasion  to bone  epidural, intrathecal, spine  to liver, lung  osteoblastic vs osteoclastic  Secondary to therapy -Varicella Zoster resulting from low WBC -Radiation Plexopathy: Brachial Plexopathy (r/o tumor reinvasion) -Neuropathy secondary to oncology therapy  Obstruction bowel or biliary system  Vertebral syndromes from compression by tumor  Headache: intracerebral tumor  Paraneoplastic syndromes
6. Nociceptive Pain  Peripheral and centrally mediated  Bradykinins, Nerve growth factor, Cytokines, ATP, Protons from dying cells  These substances activate primary afferent and awaken silent nociceptors (feed forward loop)  Primary afferent discharge leads to dorsal horn hyperexcitation and the activation of microglia  Peripheral inhibition via activation of peripheral and central opioid receptors, Cox pathways and descending modulation
9. Neuropathic pain  Damage to neurons either peripheral or central (via compression or ischemia/ hemorrhage, chemical or transection).  Peripheral damage  accumulation of abnormal sodium and calcium channels at the site of injury  Alterations to gene expression of receptors  Damaged neurons discharge spontaneously and there is cross-talk to normal fibers and recruitment of silent nociceptors  Excessive or absent discharge from primary afferents within the dorsal horn results in overall excitation an alteration in expression of NMDA receptors and functional loss of opioid and gabaminergic systems  There is resultant hyperexcitation with increased receptive fields  primary and secondary hyperalgesia, and allodynia  Dorsal columns relay predominately to thalamus, giving rise to strong autonomic responses and efferent responses
10. Visceral Pain  Diffuse, poorly organized; Patient may often complain of cramping and spasms  Silent nociceptors become activated by inflammation  Also stimulated by: ischemia, distention/contraction, and compression  Key transmitters: serotonin (peripheral and central), calcitonin-gene-related peptide, vasoactive intestinal, peptide, kinins  Dorsal horn modulation is transmitted centrally via spinothalamic to viscero-sensory cortex
12. Pharmacologic treatment  Antipyretic Analgesic- acetaminophen  NSAIDS - OTC ibuprofen - Non specific - sulindac - Cyclooxygenase II specific Celecoxib and Meloxicam  Anticonvulsant Agents  Antidepressants  Mixed mu agonists  Mu agonists  Alpha 2 agonists
13. Anticonvulsants  Mechanisms  Calcium channel antagonists: Voltage gated calcium channel is affected by binding the alpha 2 delta unit of VSCC  Sodium channel blockers  GABA –A receptor activators  Undetermined mechanism
14. Calcium channel blockers (Gabapentin and pregabalin)  Anti-hyperalgesic effects in animal models of inflammation and nerve pain (little to no effect on acute pain)  Block the alpha 2 delta subunit of the L type calcium channel  Act in the outer layers of the dorsal horn  Decrease the release of glutamate norepinephrine substance P
15. Gabapentin (Neurontin)  Developed to mimic GABA but does not bind the Gaba receptor, blocks alpha 2 delta subunit of L calcium channel in CNS  Molecular structure similar to GABA  Provides additional relief in patients oncology patients (improves analgesic efficiency) Multiple Sclerosis Spinal Stenosis  Initiate at 100mg -300mg daily  Fatigue, somnolence, dizziness, caution with renal dx
16. Pregabalin (Lyrica)  More rapid onset than gabapentin, with max efficacy at 2 weeks vs 2 months  Fewer side effects, but still caution in renal disease  Dosed : 25 – 75 mg QHS in elderly to max of 150 mg po/day  In Diabetic Neuropathy: NNT =6.3
17. Sodium Channel blockers  These are Proven therapy for trigeminal neuralgia, PHN, DN, CRPS  Inhibit development of ectopic discharges  Anti-epileptiform/Anticonvulsants  Local anesthetics  Tricyclic Antidepressants  Anti-arrhythmics
18. Carbamazepine (Tegretol)  Mech: Na channel blockade, selectively blocks active fibers with no effect on normal functioning A-delta and C-fibers  Dose Initial 100mg po bid to tid  Side effects: PANCYTOPENIA - agranulocytosis and aplastic anemia; CBC necessary every three weeks (blood tests 2-4 months) Steven Johnson Syndrome Toxic Epidermal Necrolysis Dizziness and gait disturbance  Treatment models TG neuralgia- NNT<2, NNH 24 post CVA pain
19. Oxycarbamazepine (trileptal)  Mech- Na channel blockade  Titrate to 600 mg/day  Side effects: hyponatremia (<125) dizziness, somnolence, N/V can also suppress bone marrow  Treatment models: Diabetic neuropathy, Trigeminal Neuralgia
20. Phenytoin (Dilantin)  Mech: Na channel blockade, prevents glutamate release  Dose: 100mg Bid  Side effects: Change in facial features (coarsening) Gingival hyperplasia sedation changes in motion stability  Treatment models: Still used in recalcitrant oncology related pain  Increases activity of cP450, decreasing efficacy of methadone, fentanyl, tramadol, mexiletine, lamotrigine, carbamazepine  When co-administered with antidepressants, and valproic acid, the decreased activity of p450 will produce increased concentration of phenytoin
21. Lamotrigine (lamictal)  Mech: stabilizes the slow Na channel > suppress glutamate release  Dose 25mg bid  Side effects:  Skin rash  rare Steven Johnsons Syndrome, (noted when combined with valproic acid in children)  Treatment models: TN, Diabetic Neuropathy, distal sensory polyneuropathy of HIV disease
22. Topiramate (Topamax)  Mech: Na channel blocker increases GABA activity inhibits AMPA-type excitatory glutamate receptor  Dose start 25 mg QHS  Side effects: sedation kidney stones (topiramate inhibits carbonic anhydrase) glaucoma
23. Levetiracetam (Keppra)  Mech: undetermined  Dose 250mg-500mg bid  Not metabolized by p450  Side effects asthenia, dizziness, somnolence, headache
24. Mexiletine  Dose 150 BID  Mech: Na channel blocker  Side effects: nausea blurred vision irritability  Class 1B antiarrhythmic (stabilizes membranes)
25. Valproate (Depakote)  Dose needs to be titrated with blood levels approximating 50-100 mcg/ml but these doses are never used when treating chronic pain  Mech: GABA–A receptor agonist  Side effects: CNS depression  Target treatment groups: Change in migraine therapy, suppress cns compression by tumor
26.  Mechanism local anesthetic, Na channel block  12on/12off, rotate patch  Useful near drain sites, chest tubes, recent large incisions  Side effects include dizziness and blurred vision and at concentrations of 10mcg/ml, seizure and 25 mcg/ml cardiac depression, but these plasma levels do not result from the patches Lidocaine Patch
27. Antidepressants  Anti depressants have been used to treat depression associated with chronic pain or resulting from the chronic painful condition  There are three basic categories:  TCA - example Elavil (amitriptyline)  SSRI - example Prozac (fluoxetine; rarely used in oncology patients due to serotonin syndrome)  SNRI – example Cymbalta (duloxetine)
28. TCA (Tricyclic Antidepressants)  Older forms inhibit reuptake of serotonin and norepi, increasing synaptic levels of these meds  They have independent analgesic properties at lower doses  Differ in terms of side effects:  anticholinergic, (dry mouth, constipation, blurred vision, urinary retention)  antihistamine effects (sedation)
29. TCA pharmacology  Quinidine like properties make them proarrhythmic  TCAs prolong the QT interval  TCA decrease seizure threshold  Some TCAs have documented analgesic properties  All TCAs cause urinary retention, dry mouth, postural hypotension, weight gain  Hepatic clearance involves the p450 system  Meds which compete for the enzyme will increase levels when co-administered (SSRI, cimetidine, methylphenidate)  P450 enzyme inducers will decrease serum TCA levels (phenobarbital, carbamazepine, cigarette smoking)
30. SSRI (Selective Serotonin Reuptake Inhibitors)  Lower side effect profile than TCA, but decrease seizure threshold  Associated with easy bruising and osteoporosis  Side effects include decreased libido, impotence, dystonia, akathisia, rare SIADH  Few independent pain properties  Never proven to be opioid sparing when compared to TCA  Taper off slowly
31. Serotonin Syndrome  Seen when SSRI are combined with:  mixed Mu agonists (tramadol, tapentadol)  Anti-emetics: (zofran, reglan)  narcotics: meperidine, fentanyl, pentatozine  Presents as:  Clonus, Tachycardia, Mental Status Change
32. SNRI (Serotonin and Norepinephrine Reuptake Inhibitors)  Inhibit reabsorption of serotonin and norepinephrine  Duloxetine (Cymbalta) indicated for tx of diabetic neuropathy and fibromyalgia  Starting dose: 30mg PO  Side-effects: dry mouth, dizziness, constipation, 2d6 inhibitor
33. Commonly Used Blocks for Abdominal Pain  Celiac Plexus Block  Superior Hypogastric Plexus Block  Uses:  Pancreatitis, acute and chronic  Diagnostic  Treatment of abdominal ischemia  Treatment of acute pain after arterial embolization for cancer pain  Treatment of pain secondary to upper abdominal malignancy
34. Celiac plexus block  Largest pre-vertebral plexus, para-aortic  Retroperitoneal, but anterior to the crus of the diaphragm  As an anterocrural block, the needle is approximately 1 cm anterior to the lower border of L1; will go through the aorta on the left side, depositing dye anterior to the aorta on that side  Contributing ganglia include aortico-renal and mesenteric  Covers entire ascending and transverse colon  The descending colon and rectum are not covered  Current literature review suggests that the adrenal and possibly the nerve supply to the ovary is covered by the CPB
35. Nerve supply to celiac plexus  SYMPATHETIC EFFERENT fibers become the SPLANCHNIC NERVES  Afferent sensory fibers  C type silent nociceptors which run with the above fibers  Parasympathetic fibers from the vagus nerve  Sympathetic afferents
37. Celiac Plexus Block Procedure  Patient prone on pillow, IV Sedation, monitoring including EKG, pulse ox, ABP  Lower border spines of T12 and L1  Distal end of rib 12, 45° toward midline  Needle advanced 15° cephalad, slowly under the lateral aspect of the L1 vertebral transverse process to anterior body L1
39. Injection agents  Diagnostic nerve block  30ml of dilute local anesthetic + steroid  Neurolytic  same volume of phenol or alcohol after successful block following contrast dye study  Phenol 6%-12% anesthetic hyperbaric delayed effects  Alcohol painful on injection hypobaric immediate effects  alcohol has been associated with spasm of the major spinal arteries causing transient paralysis
40. Complications  Hypotension from sympathetic block  Puncture of abdominal blood vessels  Pneumothorax  Diarrhea  Persistent Hypotension (after lysis)  Silent Abdomen  Alcohol migration across diaphragm  Intravascular alcohol uptake  Infection  Bleeding
41. Superior hypogastric plexus block  This block is indicated for the diagnosis and possibly treatment of painful conditions of the pelvis  The block is performed using fluoroscopy from the posterior approach
42. Opioids  Mu Opioid Receptor Agonist  G-protein linked receptor  Inhibits neuronal activation  Tonic release: sets inhibitory tone  Phasic release: attenuates pro-excitation  Mu, kappa, delta, and ORL-1 receptors  Exogenous ligands are all principally mu receptor agonists  Morphine, methadone, oxycodone
44. Opioids  Opioids mimic the actions of endogenous opioid peptides by interacting with mu, delta or kappa opioid receptors  The opioid receptors are coupled to G1 proteins and the actions of the opioids are mainly inhibitory  They close N-type voltage-operated calcium channels and open calcium- dependent inwardly-rectifying potassium channels  This results in hyperpolarization and a reduction in neuronal excitability  They also decrease intracellular cAMP which modulates the release of nociceptive neurotransmitters (e.g. substance P)
45. Other Treatments  Neurolytic Blocks  Antineoplastic therapies  Radiation therapy  Surgical decompression for spinal tumors  Non surgical decompression- Cryotherapy, RFA  Chemical Denervation of tumor involved areas  Augmentation of tumor involved areas  Spinal Cord Stimulation  Intrathecal Pumps
46. Neurolytic Blocks  A neurolytic block is the targeted destruction of a nerve or nerve plexus  Frequently, the term neuroablation is used to also describe the physical interruption of pain either chemically, thermally, or surgically  All neurolytic techniques cause Wallerian degeneration of the nerve axon distal to the lesion.
47. Intrathecal Pumps  FDA approved since 1980s  Important because it is estimated that up to 20% of patients have suboptimal pain control  Paradigm shift: Interventional pain management no longer last resort  Morphine: Intrathecal daily dose could be reduced by a factor 12 to 300, compared with the oral daily dose
48. Intrathecal Pumps  Intrathecal pumps deliver small doses of medication directly to the spinal fluid  It consists of a small battery-powered, programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a small catheter tunneled to the site of spinal entry  Sophisticated drug dose regimens can be instituted  Implanted pumps need to be refilled every 1 to 3 months  There is no evidence showing whether it is more clinically effective to use bolus or continuous dosing.
49. Intrathecal Pumps  Benefits:  Fixed continuous rate of infusion with bolus option for breakthrough pain  Lower doses of drug generally produce fewer adverse effects  sedation, cognitive deficits, fatigue, and constipation  Intrathecal drug administration can provide more effective analgesia than systemically administered  Early implementation may lead to improved survival (Smith, T.J. et al. 2002. Journal of Clinical Oncology)  Minimize divergence of medications
50. FDA Approved Medications  Ziconotide (prialT)  Nonopiod intrathecal peptide that acts at the substantia gelatinosa of the spinal cord  Antagonizes presynaptic N type calcium channels within the dorsal root ganglion  Morphine  Central mu agonist
52. Surgical procedures  Last resort
53. Sympathectomy  Indication: visceral pain of cancer  How: RF or chemical ablation at sympathetic chains or ganglia  Has been largely replaced by SCS
54. Dorsal Rhizotomy  Sensory input can be targeted by severing the nerve in the posterior (dorsal aspect)  This is not totally effective as some of the afferent nerve fibers travel in the ventral nerve roots
55. Cranial Nerve Rhizotomies  Rhizotomies still useful for the treatment of cranial nerve neuralgias  Trigeminal  glossopharyngeal  RF lesioning, glycerol, balloon compression  Stereotactic radiosurgery for treatment of trigeminal neuralgia is also possible, but pain relief can take two weeks to mature
56. Anterolateral Cordotomy  Target: Lateral Spinothalamic tract, ascending fibers  Surgical access via upper posterior spine  Why: treat pain of malignancy, cuts the central processes on nociceptors after they cross in anterior commissure, then ascend, therapy for lancinating pain  Results: contralateral defect in pain and temperature 2-5 levels below the lesion
57. Cingulotomy  Why- target “affective” components of pain, essentially a lobotomy procedure that was perfected by Freeman and Watts  RF lesions of bilateral anterior cingulate gyrus  Indicated for intractable pain of malignant origin  “Psychosurgery”  May be used for OCD
58. DREZ (Dorsal Root Entry Zone) Lesioning  For Brachial Neuralgia