5Opiate Induced Constipation Most common dose dependent side effect of opiates, despite mode of administration IV, IM, PO, Intrathecal, or EpiduralTolerance does not develop to this side effect15-90% of patient receiving opiates for non cancer pain develop constipationOpiates bind to receptors in the myenteric plexusWithin the longitudinal smooth muscle of the gut, opiates inhibit release of acetylcholine , thereby decreasing propulsive effects. Circular > longitudinal muscle contraction occursAs a result of increased transit time, more water is absorbed from the stoolDecreased intestinal, biliary, gastric and pancreatic secretions are observed in patients on opiatesIncreased rectal sphincter tone results from opiate administration
9Symptoms of Opiate Induced Constipation NauseaBloatingAbdominal PainDiarrhea or overflow stoolingReflux
10Management of Opiate Induced Constipation (OIC) Increase fluid uptake to 1.5 – 2.0 liters per dayRemember that opiate induced constipation results from decreased motility and increased toneSofteners and bulking agents will be inadequate to give relief, a laxative must be addedLaxatives soften hard stool by affecting water & electrolyte transfer within the small intestine and colon
11Health Behaviors to Reduce Opiate Induced Constipation (OIC) Instruct patients to :Increase fluid uptakeIncrease intake of high fiber foodsIncrease activity levels
12Oral Treatment Options for OIC Bulk LaxativesInsoluble Fiber : Bran 20 grams / daySoluble Fiber : Psyllium, MethylcelluloseOsmotic Laxatives :Polyethylene Glycol : 21 grams / dayLactulose & Sorbitol are carbohydrate laxatives which are poorly absorbed by the gutPhosphate or magnesiumStimulant (Irritant) LaxativesAnthraquinones : Cascara, Aloe, SennaCastor OilDiphenylmethanes : BisacodylChloride Channel Activators :** Lubiprostone 24 mcg. BID – FDA approved *There is some evidence that use of the mu agonist / selective norepinephrine reuptake inhibitor tapentadol is associated with a lower incidence of OIC than use of other mu agonist drugs
14Opiate Antagonists for Constipation Methylnaltrexone (Relistor):Peripherally acting mu opioid receptor antagonist, **FDA approved foropiate induced constipation**Does not cross the blood brain barrierBlocks only the peripherally mediated effects of opiates,so it does not induce withdrawalOral cecal transit times are reduced without evidence of opiate withdrawalNo known drug interactionsAdministered as a SQ injection every other day, usually works within4 hrs. of administrationDose :lbs. : 8 mg SQ every other daylbs. : 12 mg SQ every other day
15Recommendations for Treatment of OIC First Line Treatment : Softener & StimulantSecond Line Treatment : Enema / Rectal SuppositoryThird Line Treatment : Manual Evacuation following by use of a peripherally acting mu opiate antagonist
17Opioid Induced NauseaPrimarily induced by a centrally mediated effect on the brainstem medullary chemoreceptor and secondarily a peripherally mediated effect on the GI tractWhile nausea and vomiting may occur with the initiation of opioid therapy, cases of severe protracted nausea and vomiting are seldom due to opioids aloneIn the majority of cases, severe protracted nausea and vomiting is mild and can be treated with anti-emeticsMost nausea and vomiting resolves in 2 – 3 days, so decreasing the dose of the opiate may be enough to relieve symptomsChanging the route of administration of the opiate may reduce nauseaConsider substituting with the equianalgesic dose of another opiate
18Opioid Induced NauseaPremedicate with an anti emetic agent prior to dosing with the opiateH2 blockers – pepcid, zantac – reduces nausea5 HT3 blockers – odanestronDopamine antagonists : droperidol, haloperidol, metaclopramideAnti cholinergics : Scopolamine
19Opioid Induced Nausea : Rule Out Other Treatable Causes Chemotherapy (primarily cisplatin)Radiation TherapyBrain MetastasesGI MetastasesElectrolyte / Acid – Base DisturbanceInfectionElevated ICPPUDEsophagitisGastritisLiver DiseaseFearAnxietyUremia
21Opiate Induced Sedation Mediated by acetylcholineManagement of Opiate Induced Sedation :Decrease the dose or decrease dose frequency to the smallest amount necessary to achieve analgesiaRule out other etiologies for sedation, including use of other drugs, such as tricyclics or anticonvulsantsDetermine if adjuvant non – medication therapies, such as nerve blocks, epidurals, spinal cord stimulators, etc) in order to reduce the amount of medication required to achieve analgesiaOpioid rotation to a short acting agent if possible
22Donepezil (Aricept) for Opiate Induced Sedation The states of arousal, attention and respiratory regulation are in part mediated by central cholinergic activity – It is known that opiates inhibit this pathwayEnhancing cholinergic activity may improve wakefulness in opioid dependent patientsStudies :Slatkin et al, J. Pain Symp Management, 2001 : Study of 6 cancer patients taking greater than 200 mg oral morphine equivalent per day placed on Aricept had less sedation, more alertnessBruera et al, J. Pain Sympt Management, 2003 : One week open label prospective pilot study of patients on > 180 mg morphine equivalent dose placed on Aricept 5 mg po QAM. Study subjects showed improvements in sedation, fatigue, general well being, anxiety, and constipation.
23Sedation in the Setting of Respiratory Depression Seen mostly commonly with opiates which have long plasma half livesWithholding one or two doses and then decreasing the overall dose to 25% of the original dose until symptom resolution is usually sufficient and will usually avoid withdrawal
27Respiratory Depression This side effect is mediated centrally in the medullaOpiate induced respiratory depression leads to an increase in PCO2 and a decrease in the medulla’s sensitivity to carbon dioxide, which further decreases the respiratory rateConcomitant use of oral or IV opiates in combination with intrathecal or epidural opiates increases the risk of respiratory depressionAlso seen more frequently when opiates are used in conjunction with other CNS depressants, such as benzodiazepines or muscle relaxants, including Flexeril (cyclobenzaprine)When administering neuroaxial opiates, the greatest risk of respiratory depression occurs within 4 – 8 hrs and is more likely to occur with hydrophilic than lipophilic opioidsWhen respiratory depression occurs, naloxone must be administered
28Naloxone Pure opioid antagonist Blocks mu opioid receptors, which are responsible for analgesia and respiratory depressionBlocks kappa opioid receptors, which are responsible for sedation and pupillary constrictionLess effective at blocking NMDA receptors which mediate delirium & hallucinationsReverses lipophilic opiates more than hydrophilic opioids
29Naloxone for Respiratory Depression 0.4 mg Naloxone diluted in 10 ml normal saline administered in 0.5 cc (0.02 mg) IV boluses every minute until resolution of the respiratory depression OR….Naloxone 40 – 80 mcg IV Q 2 minutes, repeat every 30 minutes as needed ORContinuous infusion Naloxone 0.8 mg mixed in 250 cc normal salineContinue till respiratory rate is > 12 / minSide effects of opiate reversal : abdominal cramps, vomiting, HTN, tachycardia, seizures, chest pain, arrhythmiasIn certain patients, administration of naloxone can provoke pulmonary edemaThis effect is likely the result of reversal of opiate induced pulmonary vascular smooth muscle relaxationNaloxone induced pulmonary edema is usually seen in patients with history of CHF or ARDS
33Hot Flashes Due to Hypogonadism Hot flashes are commonly described by both men and women on opiate analgesics, due to low hormone levels secondary to hypogonadismWork Up : Prolactin Level, LH, FSH, Free and Total Testosterone Levels, Estrogen LevelsTreatment :GabapentinEffexorHormone Replacement
34Hypogonadism Isn’t All About Hot Flashes … The hypogonadism can also cause osteoporosis to developPlease remember to check your patient’s bone mineral density with a DEXA at least every two years if he / she is on chronic opiate maintenanceResearch indicates that many men on chronic opiate maintenance require medications for erectile dysfunction
39Opioid Induced Hyperalgesia Opioid-induced hyperalgesia is a condition manifested clinically as hyperesthesia (i.e., dramatically increased sensitivity to painful stimuli) and/or allodynia (i.e., pain elicited by a normally nonpainful stimulus).It occurs in some patients (and, in laboratory studies, animals) receiving chronic opioid therapy; the abnormal pain often arises from an anatomically distinct region and is of a different quality than the original pain problem
40NMDA Receptors & Opiate Induced Hyperalgesia Several mechanisms associated with opioid-induced hyperalgesia have been identified.Glutamate-associated activation of N-methyl-D-aspartate (NMDA) receptors causes spinal neuron sensitization; this pronociceptive mechanism has been implicated in the development of neuropathic pain and opioid-induced hyperalgesia.The ability of NMDA receptor antagonists such as MK801 to block opioid-associated hyperalgesia provides further evidence that NMDA receptors are involved in hyperalgesic states (King et al 2005, Mao 2006, Ossipov et al 2005).
41NMDA Receptors, CCK & Hyperalgesia The major clinical manifestation of opioid-induced tolerance and that of hyperalgesia are the same; that is, increasing opioid doses are necessary to achieve adequate analgesia (Angst & Clark 2006, King et al 2005, Mao 2006).Moreover, there are similarities in the mechanisms that cause tolerance and hyperalgesia. For example, CCK-mediated changes in the descending modulatory pathways appear to contribute to both opioid-induced tolerance and hyperalgesia (King et al., 2005).There also is evidence that tolerance and hyperalgesia share common cellular mechanisms that are related to changes in NMDA receptors (Mao et al 1994, Mao et al 2002).
42Differences Between Hyperalgesia & Tolerance Hyperalgesia is characterized by different clinical features than tolerance. These features include pain intensity that is higher than the severity of the original pain problem, pain that is poorly defined in terms of quality and location, and changes in pain threshold and tolerability.These distinct features indicate that at least some of the cellular mechanisms underlying tolerance and hyperalgesia differ between the two entities.Hyperalgesia represents increased sensitivity to pain, whereas tolerance may reflect decreased sensitivity to opioids.Most importantly, unlike tolerance, opioid-induced hyperalgesia would worsen after an increase in opioid dose, whereas pain related to tolerance would be relieved by an increase in opioid dose (Mao 2002, Mao 2006).
43Prevention of Opiate Induced Hyperalgesia Minimize use of opiates if possibleConcomitant use of NMDA receptor antagonist (Methadone) with opiate analgesic to prevent hyperalgesia from developingIf patient is refractory to use of an NMDA receptor antagonist, and still suffers from opiate induced hyperalgesia, consider the use of ketamine.
45Opiate Induced Pruritus An uncommon side effect with oral opiate administrationParenteral opiates typically produce mild pruritus, but it can be moderate – severe in a minority of patientsLocation of pruritus is usually on the face or the perineum, but can also be generalizedIn the setting of oral or IV opiate administration, pruritus is thought to be secondary to the release of histamine from mast cellsMu opiate receptors may also be involved, as administration of a mu opioid receptor antagonist can reverse pruritus, but might reverse analgesiaOpioid rotation may reduce pruritusTreatment : Antihistamines – I usually achieve success by administering Atarax (H1 blocker) and oral Zantac or Pepcid (H2 blockers)
46Pruritus Following Spinal Opiate Administration Pruritus occurs more frequently when opioids are administered via neuroaxial routeIncidence of opiate induced pruritus is 55 – 100 % in patients receiving intrathecal or epidural morphine, fentanyl, or sufentanilPruritus after neuroaxial opiate administration is typically seen within 2 – 5 hrs after dose administration and is dose relatedTolerance to this side effect develops rapidly with resolution occurring within days for those receiving spinal opioidsPruritus in the setting of spinally administered opiates is a centrally mediated problem involving excitation of the medullary dorsal horn, central migration of spinal opioids to the brainstem, and antagonism of inhibitory transmitters.Opiate induced serotonin release may be involved in centrally mediated pruritus of this typeFor pruritus resulting from spinally administered opiates, Ondansetron (Zofran), a 5 HT 3 receptor antagonist, is the best choice at a dose of 4 mg IV
48AddictionIs a primary chronic neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestationsIt is characterized by behaviors that include one or more of the followingImpaired control over drug useCompulsive useContinued use despite harmCraving
49Physical DependenceIs a state of adaptation that is manifested by a drug class specific withdrawal syndrome which may be precipitated by :Abrupt cessationRapid dose reductionDecreasing blood levels of the drugAdministration of an antagonistEveryone on opiates for a prolonged period of time develops physical dependence. This does NOT mean the patient is an addict.
50ToleranceIs a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over timeExample : Remember, if you are on methadone for a prolonged period of time that methadone auto – induces the enzymes responsible for its metabolism, so you may have to increase the doseUse of an NMDA receptor antagonist with opiate administration may prevent tolerance, which is mediated by the NMDA receptor
51Opiate Withdrawal Occurs when opiates are abruptly withdrawn Early symptoms of withdrawal include:AgitationAnxietyMyalgiasLacrimationInsomniaRhinorrheaDiaphoresisYawningBlood Pressure Elevation / Elevated Heart Rate
52Late Symptoms of Opiate Withdrawal Late symptoms of withdrawal include:Abdominal crampingDiarrheaDilated pupilsGoose bumpsNauseaVomiting
53Opiate WithdrawalIn general, opioid withdrawal does not directly cause life-threatening symptoms, seizures, or delirium.Opiate withdrawal is only dangerous in patients with moderate-severe hypertension or pre-existing seizure disorderAltered mental status, disorientation, hallucinations, and seizures, which are characteristic of DTs, are not seen in opioid withdrawal.
54Medications for Opiate Withdrawal Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone mg/d or buprenorphine 4-16 mg/d, and then tapered over days to weeks.Clonidine mg every 4-8 hours also decreases the severity of symptoms.
55State Attorneys General Recommend that you screen all your patients for risk of abuse of prescribed opiate medications prior to starting patients on an opiate regimenSOAPPORTDASTDIRECAGE AIDSISAPOngoing surveillance is required to monitor for abuse and diversion at a minimum frequency of every 3 months in most statesCOMM is used for ongoing monitoring of patients on opiate analgesicsSee links for all the tools at the following link :
56Illegal Drug Behaviors Selling prescription drugsForging prescriptionsStealing or borrowing drugs from another personInjection of oral preparationsOngoing use of illicit drugsMultiple unsanctioned drug escalationsRepeated episodes of lost prescriptionsObtaining prescriptions drugs from non medical sources
57Prescription Abuse Checklist A focus on opioid issues during clinic visits impeding progress with other treatment issues and persisting beyond the third appt.A pattern of early refills or escalating drug use in the absence of any clinical changeMultiple telephone calls or visits about opiate prescriptionsA pattern of prescription problems (lost, spilled, stolen)Supplemental sources of opiates