Complications of Opiate Therapy

Susan Stickevers, MD Residency Program Director, SUNY

Stony Brook Dept of PM&R

Opiate Induced Constipation• Most common dose dependent side effect of opiates, despite mode of

administration IV, IM, PO, Intrathecal, or Epidural • Tolerance does not develop to this side effect • 15-90% of patient receiving opiates for non cancer pain develop

constipation• Opiates bind to receptors in the myenteric plexus • Within the longitudinal smooth muscle of the gut, opiates inhibit release

of acetylcholine , thereby decreasing propulsive effects. Circular > longitudinal muscle contraction occurs

• As a result of increased transit time, more water is absorbed from the stool

• Decreased intestinal, biliary, gastric and pancreatic secretions are observed in patients on opiates

• Increased rectal sphincter tone results from opiate administration

Symptoms of Opiate Induced Constipation

• Nausea • Bloating • Abdominal Pain • Diarrhea or overflow stooling • Reflux

Management of Opiate Induced Constipation (OIC)

• Increase fluid uptake to 1.5 – 2.0 liters per day • Remember that opiate induced constipation results

from decreased motility and increased tone • Softeners and bulking agents will be inadequate to

give relief, a laxative must be added • Laxatives soften hard stool by affecting water &

electrolyte transfer within the small intestine and colon

Health Behaviors to Reduce Opiate Induced Constipation (OIC)

• Instruct patients to :– Increase fluid uptake – Increase intake of high fiber foods – Increase activity levels

Oral Treatment Options for OIC • Bulk Laxatives

– Insoluble Fiber : Bran 20 grams / day– Soluble Fiber : Psyllium, Methylcellulose

• Osmotic Laxatives :– Polyethylene Glycol : 21 grams / day– Lactulose & Sorbitol are carbohydrate laxatives which are poorly absorbed by the gut – Phosphate or magnesium

• Stimulant (Irritant) Laxatives – Anthraquinones : Cascara, Aloe, Senna – Castor Oil – Diphenylmethanes : Bisacodyl

• Chloride 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

Opiate Antagonists for Constipation

• Methylnaltrexone (Relistor):– Peripherally acting mu opioid receptor antagonist, **FDA approved for opiate induced constipation** – Does not cross the blood brain barrier– Blocks only the peripherally mediated effects of opiates, so it does not induce withdrawal– Oral cecal transit times are reduced without evidence of opiate withdrawal – No known drug interactions – Administered as a SQ injection every other day, usually works within 4 hrs. of administration – Dose :

• 84-136 lbs. : 8 mg SQ every other day • 137-251 lbs. : 12 mg SQ every other day

Recommendations for Treatment of OIC

• First Line Treatment : Softener & Stimulant • Second Line Treatment : Enema / Rectal

Suppository • Third Line Treatment : Manual Evacuation

following by use of a peripherally acting mu opiate antagonist

Opioid Induced Nausea • Primarily induced by a centrally mediated effect on the brainstem

medullary chemoreceptor and secondarily a peripherally mediated effect on the GI tract

• While nausea and vomiting may occur with the initiation of opioid therapy, cases of severe protracted nausea and vomiting are seldom due to opioids alone

• In the majority of cases, severe protracted nausea and vomiting is mild and can be treated with anti-emetics

• Most nausea and vomiting resolves in 2 – 3 days, so decreasing the dose of the opiate may be enough to relieve symptoms

• Changing the route of administration of the opiate may reduce nausea• Consider substituting with the equianalgesic dose of another opiate

Opioid Induced Nausea• Premedicate with an anti emetic agent prior

to dosing with the opiate • H2 blockers – pepcid, zantac – reduces nausea • 5 HT3 blockers – odanestron• Dopamine antagonists : droperidol,

haloperidol, metaclopramide• Anti cholinergics : Scopolamine

Opioid Induced Nausea : Rule Out Other Treatable Causes

• Chemotherapy (primarily cisplatin)

• Radiation Therapy• Brain Metastases • GI Metastases• Electrolyte / Acid – Base

Disturbance • Infection

• Elevated ICP• PUD• Esophagitis • Gastritis • Liver Disease • Fear • Anxiety• Uremia

Opiate Induced Sedation • Mediated by acetylcholine • Management of Opiate Induced Sedation :

– Decrease the dose or decrease dose frequency to the smallest amount necessary to achieve analgesia

– Rule out other etiologies for sedation, including use of other drugs, such as tricyclics or anticonvulsants

– Determine 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 analgesia

– Opioid rotation to a short acting agent if possible

Donepezil (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 pathway

• Enhancing cholinergic activity may improve wakefulness in opioid dependent patients

• Studies :– 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 alertness

– Bruera 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.

Sedation in the Setting of Respiratory Depression

• Seen mostly commonly with opiates which have long plasma half lives

• Withholding 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

Respiratory Depression• This side effect is mediated centrally in the medulla • Opiate 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 rate

• Concomitant use of oral or IV opiates in combination with intrathecal or epidural opiates increases the risk of respiratory depression

• Also 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 opioids

• When respiratory depression occurs, naloxone must be administered

Naloxone

• Pure opioid antagonist• Blocks mu opioid receptors, which are responsible

for analgesia and respiratory depression • Blocks kappa opioid receptors, which are responsible

for sedation and pupillary constriction • Less effective at blocking NMDA receptors which

mediate delirium & hallucinations • Reverses lipophilic opiates more than hydrophilic

opioids

Naloxone 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 OR• Continuous infusion Naloxone 0.8 mg mixed in 250 cc normal saline • Continue till respiratory rate is > 12 / min• Side effects of opiate reversal : abdominal cramps, vomiting, HTN, tachycardia,

seizures, chest pain, arrhythmias• In certain patients, administration of naloxone can provoke pulmonary edema • This effect is likely the result of reversal of opiate induced pulmonary vascular

smooth muscle relaxation • Naloxone induced pulmonary edema is usually seen in patients with history of

CHF or ARDS

Hot Flashes Due to Hypogonadism • Hot flashes are commonly described by both men

and women on opiate analgesics, due to low hormone levels secondary to hypogonadism

• Work Up : Prolactin Level, LH, FSH, Free and Total Testosterone Levels, Estrogen Levels

• Treatment :– Gabapentin – Effexor – Hormone Replacement

Hypogonadism Isn’t All About Hot Flashes …

• The hypogonadism can also cause osteoporosis to develop

• Please remember to check your patient’s bone mineral density with a DEXA at least every two years if he / she is on chronic opiate maintenance

• Research indicates that many men on chronic opiate maintenance require medications for erectile dysfunction

Opioid 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

NMDA 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).

NMDA 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).

Differences 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).

Prevention of Opiate Induced Hyperalgesia

• Minimize use of opiates if possible • Concomitant use of NMDA receptor

antagonist (Methadone) with opiate analgesic to prevent hyperalgesia from developing

• If patient is refractory to use of an NMDA receptor antagonist, and still suffers from opiate induced hyperalgesia, consider the use of ketamine.

Opiate Induced Pruritus • An uncommon side effect with oral opiate administration • Parenteral opiates typically produce mild pruritus, but it can be moderate

– severe in a minority of patients • Location of pruritus is usually on the face or the perineum, but can also be

generalized • In the setting of oral or IV opiate administration, pruritus is thought to be

secondary to the release of histamine from mast cells • Mu opiate receptors may also be involved, as administration of a mu

opioid receptor antagonist can reverse pruritus, but might reverse analgesia

• Opioid rotation may reduce pruritus • Treatment : Antihistamines – I usually achieve success by administering

Atarax (H1 blocker) and oral Zantac or Pepcid (H2 blockers)

Pruritus Following Spinal Opiate Administration• Pruritus occurs more frequently when opioids are administered via neuroaxial

route • Incidence of opiate induced pruritus is 55 – 100 % in patients receiving intrathecal

or epidural morphine, fentanyl, or sufentanil • Pruritus after neuroaxial opiate administration is typically seen within 2 – 5 hrs

after dose administration and is dose related • Tolerance to this side effect develops rapidly with resolution occurring within 1 - 2

days for those receiving spinal opioids • Pruritus 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 type

• For 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

Psychological & Physiological Concerns

• Tolerance • Physical Dependence • Addiction • Pseudoaddiction

Addiction

• Is a primary chronic neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations

• It is characterized by behaviors that include one or more of the following – Impaired control over drug use– Compulsive use – Continued use despite harm – Craving

Physical Dependence • Is a state of adaptation that is manifested by a drug

class specific withdrawal syndrome which may be precipitated by :– Abrupt cessation – Rapid dose reduction– Decreasing blood levels of the drug – Administration of an antagonist

• Everyone on opiates for a prolonged period of time develops physical dependence. This does NOT mean the patient is an addict.

Tolerance • Is 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 time

• Example : 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 dose

• Use of an NMDA receptor antagonist with opiate administration may prevent tolerance, which is mediated by the NMDA receptor

Opiate Withdrawal

Occurs when opiates are abruptly withdrawn

• Early symptoms of withdrawal include:1. Agitation2. Anxiety3. Myalgias 4. Lacrimation5. Insomnia6. Rhinorrhea7. Diaphoresis 8. Yawning9. Blood Pressure Elevation / Elevated Heart Rate

Late Symptoms of Opiate Withdrawal

• Late symptoms of withdrawal include:– Abdominal cramping– Diarrhea– Dilated pupils– Goose bumps– Nausea– Vomiting

Opiate Withdrawal• In 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 disorder

• Altered mental status, disorientation, hallucinations, and seizures, which are characteristic of DTs, are not seen in opioid withdrawal.

Medications for Opiate Withdrawal

• Opioid withdrawal is treated with a long-acting opioid agonist, such as methadone 20-35 mg/d or buprenorphine 4-16 mg/d, and then tapered over days to weeks.

• Clonidine 0.1-0.2 mg every 4-8 hours also decreases the severity of symptoms.

State Attorneys General • Recommend that you screen all your patients for risk of abuse of prescribed opiate

medications prior to starting patients on an opiate regimen– SOAPP– ORT – DAST– DIRE– CAGE AID– SISAP

• Ongoing surveillance is required to monitor for abuse and diversion at a minimum frequency of every 3 months in most states– COMM is used for ongoing monitoring of patients on opiate analgesics

• See links for all the tools at the following link :http://pain-topics.org/opioid_rx/risk.php#AssessTools

Illegal Drug Behaviors

• Selling prescription drugs

• Forging prescriptions • Stealing or borrowing

drugs from another person

• Injection of oral preparations

• Ongoing use of illicit drugs

• Multiple unsanctioned drug escalations

• Repeated episodes of lost prescriptions

• Obtaining prescriptions drugs from non medical sources

Prescription 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 change

• Multiple telephone calls or visits about opiate prescriptions

• A pattern of prescription problems (lost, spilled, stolen)

• Supplemental sources of opiates

Thanks for Your Attention

• Questions ?