2 nd Cancer Pain Symposium Opiate Related Side Effects: Focus

							2nd Cancer Pain Symposium
Opiate Related Side Effects:
   Focus on Constipation

             Lydia Mis, PharmD, BCOP
            Clinical Oncology Pharmacist
                     June 6, 2008
              Duke University Hospital
                  School of Nursing
               Objectives

   List the common toxicities associated
    with opioid analgesic use
   Understand the mechanisms
    associated with opioid toxicity
   Describe pharmacologic and non-
    pharmacologic means by which to
    treat and prevent opioid associated
    toxicities
         Opioid Induced Nausea
Pathophysiology              Implications
 Circulating blood           Tolerance to the
   opiates activate             nauseating effects may
   receptors in the             occur
   chemoreceptor trigger      Slow titration to a
   zone located outside of      therapeutic dose may
   the blood brain barrier      decrease likelihood of
 This transmits a signal       developing nausea
   to the vomiting center,
   located in the medulla
   of the brain
       Opiate Induced Nausea

   Prevention
    • Make antiemetics available with opioid
      prescription and slowly titrate up on doses
   Assessment of alternate causes
    • Constipation, CNS pathology, chemotherapy,
      radiation therapy, GI obstruction
   Treatment
    • Consider non-opiates adjuncts as alternatives
    • Antiemetic therapy
       Opioid Induced Nausea

   Nausea persistent for > 1 week
    • Reassess cause and severity of nausea
    • Change opioid (rotation)
   Refractory nausea
    • Persists after above has been tried
    • Reassess cause and severity of nausea
    • Consider neuroaxial analgesia or neuroablative
      techniques to potentially reduce opiate dose

             NCCN Practice Guidelines in Oncology -
                  v.1.2007 Adult Cancer Pain
      Opioid Induced Sedation

   Preventive measures
    • Initiate opioids at lowest possible doses tailored
      for patient opioid history and clinical status
    • If dose needs to be increased, do so by 25-50%
    • Counsel pts -  dose →  sedation x 24-72 hrs
   Persistent sedation > 1 week after
    initiation of opioids
    • Evaluate for other causes of sedation
        CNS pathology, other sedating medications,
         hypercalcemia, dehydration, sepsis, hypoxia
          Opioid Induced Sedation

   Persistent sedation > 1 wk after start
    •   Consider ∆ of opioid or ↓ dose to lowest possible
    •   Consider adjuvant analgesics
    •   Consider lower dose more frequently to ↓ peaks
    •   Consider CNS stimulants
          Caffeine, methylphenidate, dextroamphetamine, modafinil

   Refractory sedation
    • Reassess cause and severity & consider neuroaxial
      analgesia or neuroablative techniques
                      NCCN Adult Cancer Pain v.1.2007
      Opioid Induced Delirium

   Assess for other causes of delirium
    • Hypercalcemia, CNS pathology, brain metastasis,
      other psychoactive medications
   Consider change opiate or adjuvant
    analgesic to decrease dose
   Consider neuroleptic agent
    • Antipsychotics: haloperidol, risperidone, etc

              NCCN Practice Guidelines in Oncology
                  Adult Cancer Pain v.1.2007
     Opioid Induced Motor and
      Cognitive Dysfunction
   Stable dose of opioids > 2 weeks are
    not likely to interfere with
    psychomotor and cognitive function
    • Monitor closely during analgesic administration
      and titration
    • Patients should not drive during initial titration
      and should be counseled not to drive x 48 hours
      after dose increase
               NCCN Practice Guidelines in Oncology
                   Adult Cancer Pain v.1.2007
     Opioid Toxicity Syndrome

   Use of extremely high doses of opioids
    (> 100 mg/hr morphine or equivalent)
   Hyperalgesia, myoclonic jerks, AMS
    •  Dose of opioid  pain not analgesia
    • Associated with dehydration, renal impairment,
      debilitated patients with advanced disease
   Treatment: opioid rotation and NMDA
    antagonists (methadone or ketamine)
          NCCN Practice Guidelines Adult Cancer Pain v1.2007
                J Clin Oncol 2007;25(28):4497-4498
    Opioid Induced Respiratory
            Depression
   Use reversal agents sparingly
   If respiratory problems or acute MS ∆
    • Naloxone Intravenous Administration
    • 0.4 mg diluted in 10 mls NS
    • Give 1 ml (0.04mg) Q 30-60 seconds until
      improvement in symptoms is noted x 10 minutes
    • Note: half-life of opioid >>> half-life of naloxone
   If no response, consider alternative
    causes of respiratory depression
                 NCCN Adult Cancer Pain v.1.2007
    Opioid Induced Constipation

   WD is a 44 yo female admitted to the
    inpatient 9300 service with abdominal
    pain
   Metastatic gastric cancer (liver, bone)
    with delays in chemotherapy d/t
    increased abdominal pain
    unresponsive to current pain regimen
    of OxyContin 40 mg TID and prn
    oxycodone
    Opioid Induced Constipation

   Other meds on admission included
    • Protonix, ativan, cipro/augmentin, ritalin, zofran,
      neurontin
    • Senna 1 tab BID, colace, lactulose, fleets
   Patient states maintaining hydration &
    urination, no BM x 7 days PTA
   CT abdomen ordered
   Chemistries notable for Ca2+ 12.3
Opioid Induced Constipation
Opioid Induced Constipation
    Opioid Induced Constipation

   Patient CT Scan/KUB suggestive of
    severe hypercalcemia or opioid
    induced constipation
   Aggressively managed with enemas,
    oral laxatives, stool softeners, osmotic
    agents, IV hydration and zometa
   Discharged home on same opioid dose
    and aggressive bowel regimen with
    instructions
        Opioid Induced Constipation
Cause                          Prevention
 Dehydration, electrolyte      Hydration/fluids, exercise
   abnormalities                Stool softener
 Opioid analgesics –              • Sorbitol, lactulose, docusate,
   directly acting on opioid         miralax, SMOG enemas
   receptors in the gut           Stimulant laxatives
 Ondansetron & other              • Bisacodyl, senna
   agents causing                 Saline laxatives
   constipation                    • MOM, fleets, mag citrate
 Chemotherapy agents             Prokinetic agents
   known to affect nerve           • Metoclopramide
   conduction in the gut
       Opioid Induced Constipation
 Evaluation                       Treatment
 Patient history                  Sorbitol/lactulose 30 ml
 Listen for bowel sounds            Q3h x 3 then prn
 R/O obstruction - Scans          Bisacodyl 10-15 mg PO

 Rectal exam – Impaction?
                                     or 10 mg PR daily
                                   Docusate 200 mg BID
 R/O organic causes
                                     or Miralax 17 gm po
    • Hypercalcemia, treatment
      related constipation,          BID
      hydration, hypothyroidism    Senna-S 2 tab po BID
   Peritoneal carcinomatosis        “Fiber + Opiate = Brick”
   Abdominal adenopathy
                                      NCCN v.1.2007, J Pain Symptom Manage
                                               2008;35(1):103-113
    Opioid Induced Constipation
   Methylnaltrexone (naloxone derivative)
    • New kid on the block for treatment and
      prevention of opioid induced constipation
    • Peripherally-acting mu-opioid receptor antagonist
      for use in patients with advanced illness
      receiving palliative care
    • Does not reverse analgesia
    • Contraindicated if patient has bowel obstruction
   Typically dosed 8-12 mg (wt based)
    SQ every other day (up to Q 24 hours)
         http://www.wyeth.com/hcp/relistor/landing, accessed 5/08
    Opioid Induced Constipation

   Causes intense
    laxation within 30
    minutes of dose
    • Close proximity to
      proper facilities
      needed
   DC for severe or
    persistent diarrhea
    or if need for
    systemic opioids
    are eliminated