Cognitive Effects of Opioid Therapy. Cognitive Function. Prevalence. Delirium (DSM IV) Significance of Cognitive Effects

Transcription

1 Cognitive Effects of Opioid Therapy Jeannine M. Brant RN, MS, AOCN St.Vincent Healthcare Billings, MT Cognitive Function! Brain s acquisition! Information system Processing Storage Retrieval! Includes: dementia, delirium! Not synonymous with level of consciousness Prevalence! Which population?! How is it defined?! Hospitalized oncology patients 14-77%! Palliative Care patients 20-44% Average 6-16 days before death Folstein et al. (1983). Cognitive assessment of cancer patients. Cancer; 53 (suppl 10), Leipzig et al. (1987). Reversible, narcotic-associated mental status impairment in patients with metastatic cancer. Pharmacology, 35, Lawlor et al. (1997). The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer, 79, Gagnon et al. (2000). Delirium in terminal cancer: a prospective study using daily screening, early diagnosis, and continuous monitoring. J Pain and Symptom Manage, 19, Significance of Cognitive Effects! Quality of Life Physical Psychological Sociological Spiritual! Fear Opiophobia Impact on prescribing behaviors! Lack of Subjective Assessment Delirium (DSM IV)! A disturbance in consciousness and alertness with associated disturbance in the sleep wake cycle Changes in cognition Altered psychomotor activity Emotional lability Fluctuates during the day Usually attributed to > 1 etiology

2 Dementia v Delirium Risk Factors for Delirium Onset Course Consciousness & orientation Attention & memory Psychosis Delirium Acute Fluctuating Clouded, disoriented Poor short term memory; inattention Common Dementia Insidious Steadily progressive Clear until late stages Poor short term Memory without marked inattention Less common! Diagnosis of dementia! Advanced age! Infection/sepsis! Hospitalization! Isolation/unfamiliar surroundings! Surgery/post op status! MI, CHF! Acute blood loss! Subcortical CVA! Fluid / electolytes! Azotemia! Constipation or diarrhea! Fracture! Sleep deprivation! Malignancy! ETOH/substance abuse! Medications! Unrelieved pain ACUTE CHANGE IN MS Types of Delirium Antiparkinsonian drugs Corticosteroids Urinary incontinence drugs Theophylline Emptying drugs CV drugs H 2 -blockers Antimicrobials NSAIDS Geropsychiatric drugs ENT drugs Insomnia drugs Narcotics Muscle relaxants Seizure drugs! Hypoactive Sedative, subtle Associated with opioid initiation, dehydration! Hyperactive Agitation, neurotoxicity association (myoclonus, hyperalgesia, allodynia, perceptual disturbances) Associated with chronic opioid use, metabolite accumulation Meagher et al. (1998). Relationship between etiology and phenomenologic profile in delirium. J Geriat Psychol Neurol, 11, Ross et al. (1991). Delirium: phenomenologic and etiologic subtypes. Int Psychogeriatric, 3, Pathophysiology! Biochemical changes caused by the opioid Alterations in neurotransmitters! Opioid metabolites! Renal impairment! Lack of tolerance! Hepatic impairment? Assessment of Opioid-Induced Cognitive Effects

3 Cognitive Assessment One of the main reasons for missing the diagnosis of cognitive impairment or delirium is the failure to regularly conduct an objective cognitive assessment. Lawlor (2002). The panorama of opioid-related cognitive dysfunction in patients with cancer. Cancer, 94, ! Mini-mental State Examination Detection of cognitive deficits! Confusion Assessment Method (CAM) Brief assessment tool! Memorial Delirium Assessment Scale (MDAS) Measures the severity of delirium! Delirium Rating Scale (DRS) Severity scale Inouye et al. (1990)., Clarifying confusion: the confusion assessment method. A new method for detection of delirium, Ann Int Med, 113, Breitbart et al. (1997). The memorial delirium assessment scale. J Pain Symptom Manage, 13, Cognitive Assessment Scales! Mini-mental State Examination 11 questions Orientation, Memory registration, Attention and Concentration, Memory recall, Language! Confusion Assessment Method 9 questions for the nurse to ponder Diagnostic Algorithm: Acute Onset and Fluctuating Course, Inattention, Disorganized Thinking, Altered Level of Consciousness Assessment Domains! Awareness and interaction! Cognitive capacity! Thoughts and speech! Perception! Psychomotor activity! Delusions! Sleep pattern! Emotional! Temporality Lawlor (2002). The panorama of opioid-related cognitive dysfunction in patients with cancer. Cancer, 94, Driving Issues! Quality of life issue! N=24 cancer patients on stable doses of morphine and 25 pain free patients! Morphine group performed more poorly! No significant differences between two groups Preventing Opioid-Related Cognitive Effects Vaino et al. (1995). Driving ability in cancer patients receiving long-term morphine analgesia. Lancet, 346,

4 Steps for Prevention 1. Ongoing cognitive assessment. 2. Start low and go slow. 3. Use benzodiazepines and psychotropic agents with caution. 4. Maintain adequate hydration if possible. 5. Choose opioids wisely! 6. Use adjuvants to decrease opioid requirements and provide better pain control. Opioids Impact on Cognitive Function! Avoid the obvious Meperidine, propoxyphene! Morphine metabolites M3G and M6G! Hydromorphone metabolite H3G? role! Fentanyl case reports! Methadone Cumulative effect with protein binding may contribute to cognitive effects Case reports of cognitive impairment Vigano et al. (1996). Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators. Pain, 67, Bruera & Pereira. (1997). Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain. Pain, 69, Morphine Metabolites Morphine Metabolites! Morphine-3-glucuronide (M3G) conjugation accounts for over 50% antagonizes analgesic effect of morphine and M6G? neurotoxic side effects! Morphine-6-glucuronide (M6G) conjugation accounts for over 5% more potent analgesic activity than morphine contributes to overall analgesic effect! Higher concentrations of M3G and M6G after development of delirium! Variable with route of administration 1st pass hepatic glucuronidation higher M3G and M6G/morphine plasma concentration ratio potentially more side effects with oral route! Variable with repeated administration results in accumulation of M6G and greater contribution to the analgesic effect and potentially more sedative side effects Morita et al. (2002). Increased plasma morphine metabolites in terminally ill cancer patients with delirium: an intraindividual comparison. J Pain Symptom Manage 23, Influence of Renal Impairment on Cognitive Function! Role of renal excretion elimination of active drugs and metabolites! Morphine elimination of morphine unimpaired accumulation of M3G and M6G - related to creatinine clearance! Contribution to cognitive impairment and overall side effects Be Careful with Duragesic! Advantages: easy route,? constipation! 25 mcg Duragesic = approximately 75 mg oral morphine! Do not use on opioid naïve patients!! Elderly have higher fat: muscle ratio that can prolong the half-life of lipophilic drugs! Naloxone drip needed for overdose Ashby et al., (1997). Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage, 14,

5 Methadone Advantages Methadone Disadvantages! No known active metabolites! Most of drug is protein bound resulting in a slow release - long duration of action! NMDA activity may be beneficial to decrease tolerance less drug titration and inhibit neuropathic pain! Lack of known neurotoxic metabolites! Cost effective! Large inter-individual variations! Variations in individual patients from day to day and week to week!! Methadone bound to Alpha 1-acid glycoprotein (AAG) Can be displaced from AAG binding sites by propanolol, chlorpromazine, prochlorperazine, thioridazine, and imipramine enhance methadone effectiveness Mercadante et al. (1998). Morphine versus methadone in the pain treatment of advanced cancer patients followed up at home. J Clin Oncol, 16, Methadone Disadvantages! Renal clearance related to urinary ph urine ph > 6 - clearance decreases (toxicity potential) urine ph < 6 - clearance increases! Phenytoin, spironolactone, verapamil, estrogen high clearance! Amitriptylline low clearance! Malignant disease, > 65 low clearance Opioid Dosing and Titration! Start low and go slow especially in the elderly! Perform titration after reaching steady state Average 4-5 half-lives for IR opioids Average 2-3 days for CR opioids (or >)! Titrate 24 hour dose by 25-33%! Keep breakthrough dose at approximately 10-20% - higher with severe incident pain! Consider dose reduction for cross tolerance 50-75% with good pain control 0-25% with poor pain control Cherny & Foley (1996). Nonopioid and opioid analgesic pharmacotherapy of cancer pain. Hematol Oncol Clin N Am, 10, Management of Opioid-Related Cognitive Effects Managing Hypoactive Delirium! Use of psychostimulants Methylphenidate! mg doses upon initiation, especially elderly Dextroamphetamine Pemoline! Chewable tablets available, risk of hepatotoxicity Modafinil! Side effects: agitation, aggravation of perceptual disturbance

6 Managing Hyperactive Delirium! Discontinue medications thought to exacerbate delirium! Pharmacologic management! Opioid rotation! Route rotation! Nursing interventions! Family support Pharmacologic Management! Haloperidol! Chlorpromazine! Lorazepam! Methotrimeprazine! Midazolam! Risperidone! Olanzapine Opioid Rotation! Consider change in opioid if analgesia is ineffective after aggressive titration! Consider change in opioid for deleterious side effects Cognitive impairment Nausea and vomiting Constipation? treat with softener/stimulant Other DeStoutz et al. (1995). Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage, 9, Bruera et al. (1995). Changing pattern of agitated impaired mental status in patients with advanced cancer: associateion with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage, 10, Morphine to Oxycodone! Two randomized, double blind, crossover studies! Improvement in mental state, sedation with oxycodone! Less perceptual disturbance with oxycodone Kalso et al., (1990). Morphine and oxycodone in the management of cancer pain: plasma levels determined by chemical and radioreceptor assays. Pharmacol Toxicol 67, Heiskanen & Kalso, (1997). Controlled-release oxycodone and morphine in cancer related pain. Pain, 73, Route and Cognitive Function! 1 st pass effect leads to greater accumulation of opioid metabolites! As the route is closer to the opioid receptors, the dose decreases Oral morphine 30 mg Parenteral morphine 10 mg Epidural morphine 1 mg Intrathecal morphine 0.1 mg Parenteral Opioid Rotation! Use equianalgesic conversion chart as a guide! Includes IV and subcutaneous routes morphine, hydromorphone, fentanyl! Determine hourly infusion rate! Adjust rescue doses at 25-50% of hourly rate, higher for incident pain! Rescue doses may be administered every minutes

7 Spinal Anatomy Epidural Space Arachnoid Membrane Intrathecal Space (Subarachnoid Space) Intraspinal Opioid Delivery Systems Dura Pia Mater Spinal Cord Nerve Root Pump Intraspinal Catheter! Impantable pump! Tunnelled catheters! Delivery to epidural or intrathecal space! Improvement in mental clarity! Improvement in sedation! Potential improvement in comfort Nursing Issues Family Support! Loss of subjective input for symptom assessment! Inability to provide informed consent! Advance care planning! Nurse:patient ratio! Safety issues! Use of restraints! Distress! Anxiety! Fatigue! Home care issues safety! Reduced level of communication! Overall impact on quality of life! Family counseling and support groups Case Study! 68 year-old man! Metastatic prostate cancer! Active in the community Fund raising Symphony American Cancer Society Case Study Problem of Pain! Metastatic lesions throughout spine Primarily lumbar and thoracic region Hormone refractory Undergoing radiation therapy! Pain management Implantable intrathecal pump 3 years - hydromorphone Morphine CR 30 mg q 12 hours MSIR 15 mg q 2-3 hours prn

8 Pain Crisis Delirium Crisis! Acute exacerbation of pain during second day of XRT! Opioid titration 100 mg q 12 hours MSIR 30 mg q 2-3 hours prn! Other medications Gabapentin 1200 mg/day Celebrex 200 mg/day Lexapro 10 mg/day! Acute cognitive changes 48 hours after opioid titration Inattention, confusion, restlessness Family up with patient throughout the night Admitted to hospital! Laboratory Values to Consider Creatinine 1.4 Electrolytes: Na+ 145, K+ 4.8! CT head negative Assessment of Delirium Outcome! Initial Medications Haldoperidol Lorazepam Morphine gtt! Pain Consult! Psychiatric Consult! Assessment Acute delirium related to rapid opioid titration! Plan Discontinue all medications Begin olanzapine and hydromorphone! Mentation improved over the next week 1 st restlessness subsided 2 nd focus improved 3 rd memory and interaction! Patient resumed normal activities in the community within 6 weeks! Patient died 6 months later Happy Campers