Opioids for Pain: Giving the Right Drug at the Right Dose at the Right Time

Curt Gedney, M.D.

Diplomate, American Board of Hospice and Palliative Medicine

Palliative Care Physician, St. Luke’s RMC Boise/Meridian

Primary reference: http://www.eperc.mcw.edu/EPERC/FastFactsIndex

Opioids for PainPart One

Types of Pain Opioid Receptors Types of Analgesics The WHO Ladder of Pain Management Dose Escalations Dose Conversions

Opioids for PainPart Two

Opioids: Special ConsiderationsSublingual Morphine

Transdermal Fentanyl

Transmucosal Fentanyl

Methadone

Opioid Infusions

Opioid Side Effects: Delirium & Neurotoxicity

Major Categories of Pain

1. Nociceptive– CNS and peripheral afferent pathways modulated via spinal cord (dorsal horn)

– Somatic– aching, constant, localized, e.g. musculoskeletal– Visceral– sharp, crescendo/decrescendo, e.g. cholecystitis,

renal stones, intestinal obstruction, MI

2. Neuropathic– ischemia, destruction or encroachment of nerve by disease or tumor

paroxysmal shooting or shock-like pain on a background of burning, aching sensation

Major Categories of Pain

3. Inflammatory– response to tissue damage that potentiates pain

4. Soft tissue pain– pressure ulcers, burns 5. Intracranial pressure pain– brain tumor

edema and hemorrhage

Types of Neuropathic Pain

Deafferentation– phantom-type pain, usually localized numbness, tingling or burning sensation

Allodynia– pain resulting from a non-noxious stimulus to normal skin, e.g. pain on light touch or placement of clothing

Dysesthesia (continuous)– an unpleasant abnormal sensation produced by a normal stimulus, e.g. constant burning of the hand due to malignant brachial plexopathy

Types of Episodic Pain

1. End of dose failure– Dose of medication does not last the desired or prescribed

time parameters

2. Incident pain– Pain on movement or with activity

3. Breakthrough pain– Crescendo (escalating) pain superimposed over stable or

managed chronic pain Coluzzi, PH, Cancer Pain Management: Newer Perspective on

Opioids and Episodic Pain. Am J Hospice and Palliative Care. 1998:13-22.

Opioid Pharmacology:Receptor Site Theory

Opioid: Narcotic or opiate-like drugs; includes natural, synthetic and endogenous substances

Receptor sites: There are several opioid receptor sites: mu (beta-endorphins), kappa (dynorphins) and delta (met- & leu-enkephalins).

Mu Receptors 1 & 2

Effect Location1. Analgesia (robust) 1. Mid-brain/SC

2. Respiratory depression 2. Medulla

3. Inhibits GI motility 3. Intestines

4. Euphoria 4. Limbic system

Kappa Receptors 1,2 & 3

Effect Location

Analgesia (mild) Spinal cord

Inhibits GI motility Intestines

Diuresis Pituitary gland

Delta Receptors 1 & 2

Effect Location

1. Analgesia (minor) 1. Spinal cord

2. Tolerance 2. Unknown

3. Seizures 3. Striatum/cortex

Drugs and Receptor Activation

There are three opioid receptor subtypes: mu, kappa and delta.

The opioid receptor subtype’s location helps explain its function

The mu opioid receptor subtype produces the strongest analgesic response.

Major anesthetics like fentanyl, morphine, oxycodone, hydromorphone, and tramadol predominantly activate the mu opioid receptor.

Receptor Affinity of Opioid Analgesics

Receptor: mu delta kappa NMDA Morphine A Fentanyl A Hydromorphone A Oxycodone A A? Methadone A A A Pentazocine A Stadol, Nubain A Ketamine A? A? A Dextromethorphan A? A? AA= strong agonist

N-Methyl D-Aspartate Antagonists/Inhibitors

NMDA Antagonists block amino acid glutamate from binding to NMDA receptors, reducing the depolarization of spinal cord neurons. The continued firing of these neurons causes hyperalgesia. This hypersensitivity to a painful stimulus causes a “windup” phenomenon, a progressive increase in depolarization spikes that causes a single summation spike and the spontaneous firing of neurons that can persist for minutes.

NMDA Inhibitors

Reduce the occurrence of “windup” and decrease morphine tolerance at the mu receptor site. These drugs work the same way as tricyclics for neuropathic pain by preventing the uptake of serotonin and norepinephrine.

Methadone– oral, IV/SC Ketamine- IV/SC and oral,using parenteral solution Dextromethorphan Memantine HCl (Namenda) Venlafaxine and Duloxetine

Types of Analgesics

1. Non-opioid or non-steroidal anti-inflammatory drugs (NSAIDS)—work primarily at the peripheral nervous system level

– A. OTC: ASA, acetaminophen, ibuprofen– B. Prescription: ibuprofen, naproxen, indomethacin, etc.

2. Opioids work primarily at the CNS level– A. Opioid agonists: morphine, meperidine, hydromorphone,

fentanyl (Duragesic), levorphanol (Levo-Dromoran), oxymorphone (Numorphan), oxycodone, tramadol, codeine

– B. Opioid agonist-antagonists: pentazocine (Talwin), nalbuphine (Nubain), butorphanol (Stadol), buprenorphine (Buprenex)

Types of Analgesics-2

3. Adjuvant analgesics-- various actions– A. Anticonvulsants, e.g. phenytoin, carbamazepine,

valproate, gabapentin, pregabalin – B. Antidepressants, e.g. tricyclics—amitriptyline,

desipramine; SNRIs—venlafaxine , duloxetine – C. Others: steroids, Baclofen, eutetic mixture of local

anesthetics (EMLA, lidocaine, lidoderm), IV Lidocaine, dextromethorphan, bisphosphonates

Peralta A: Pain Management in the Elderly. International Jour of Pharmaceutical Compounding, May/June 2004; 8(3):187-192.

WHO Analgesic Ladder

MILD (1-3) NSAID & mild analgesics: COX 1&2, propoxyphene, APAP, ASA

MODERATE (4-7) Opioids, NSAIDS +/- adjuvants: oxycodone, codeine, tramadol, COX 1&2

SEVERE (8-10) Opioid, NSAID & Adjuvants: morphine, meperidine, methadone, fentanyl, oxycodone

World Health Organization. Cancer Pain Relief (2nd ed.), 1996

Oral Opioid Dosing Intervals

Short-acting agents (morphine, oxycodone, hydromorphone, codeine) have a peak analgesic effect in 60-90 min. with a total duration of analgesia of 2-4 hr.

AHCPR Clinical Practice Guidelines (1994) recommends dosing intervals of 3-4 hrs.

These agents may be dosed as often as every 2 hrs in pts with normal renal function.

If agents are combined with APAP and given every 4 hrs, a long-acting opioid should be prescribed.

Use of Opioids in Pain Management

Since opioids like morphine have a short half-life (t1/2) of 60 to 90 minutes, they reach steady state within 4-5 half-lives. Once steady state is achieved, you can titrate the dose up by 50-100% within 24-48 hours. Once the patient’s pain is controlled, i.e. pain rating of 0-2, you can convert the immediate release opioid to long acting opioid for pain.

Note: It is imperative to initiate a bowel regimen when starting opioid therapy.

Oral Opioid Orders:Good and Bad Examples

Tylenol #3 1-2 po q4-6 hr prn mod pain, and Percoset 1-2 po q4-6 prn severe pain

1. Short-acting opioids rarely last 6 hrs. 2. only one opioid/non-opioid combo should be

ordered at a time, assess for response, then change if needed

3. Subjective ratings of pain by nurses are inaccurate; only the pt knows the truth

4. Be careful not to exceed 4 gm/d APAP Preferred order: Percoset 1 po q4 hr prn pain

Oral Opioid Orders-2

MS Contin 60 mg q6 hr and Duragesic patch 25 mcg/hr q72 hr None of the oral long-acting products should be prescribed less

than q8 hr, and q12 hr dosing is preferred Don’t use two different long-acting products at the same time.

Instead, always order a short-acting product for breakthrough pain.

Duragesic is a poor choice for poorly controlled pain. It can be safely dose escalated only every 2-3 days.

Preferred order: MS Contin 90 mg q12 hr and MSIR 15 mg 1-2 q4 hr prn pain

Opioid Dose Escalation

Ms. B is on a morphine drip at 5 mg/hr for cancer pain. Her physician has written an order to “increase drip by 1 mg/hr, titrate to comfort”. Her nurse increases the drip to 6 mg/hr when she complains of pain. Thirty minutes later she still has no relief. What’s the problem?

Opioid Dose Escalation-2

Opioids, like other drugs, should be dose escalated on the basis of a percentage increase. Going from 5 to 6 mg is only a 20% increase.

Pts generally do not notice a change in analgesia when dose increases are less than 25%

For mod to severe pain, increase by 50-100% For mild to mod pain, increase by 25-50% Do not increase basal infusion rate (or long-acting

oral opioids) more than 100% at a time or more often than every 6-8 hrs.

Opioid Equianalgesic Table

Morphine 30 mg po 10 mg IV Hydrocodone 30 mg Oxycodone 20 mg Hydromorphone 7.5 mg 1.5 mg IV Meperidine 75 mg IM/IV Fentanyl 15 mcg/hr IV/TD Methadone see Methadone table

Calculating Opioid Dose Conversions

Morphine 10 mg IV = 30 mg oral = Hydromorphone 7.5 mg oral = 1.5 mg IV

1. Change route, keeping drug the same Change 90 mg q12 ER Morphine to Morphine IV by continuous infusion

24-hr oral Morphine dose = 180 mg po Convert to IV: 180/3 = 60 mg IV Hourly infusion rate = 60/24 = 2.5 mg/hr Rec: if a new drug, start at 50% of calculated dose to

account for variation in first pass clearance and incomplete cross-tolerance.

Calculating Conversions-2

2. Change drug, keep same route Change 90 mg q12 ER Morphine to oral

hydromorphone 24-hr oral Morphine dose = 180 mg po Hydromorphone dose = 180/4 = 45 mg po Rec: start new opioid at 50% of calculated

equianalgesic dose for possible incomplete cross-tolerance

Reduce dose 50% = 22 mg/24 hr = 4 mg q4

Calculating Conversions-3

3. Changing drug and route Change 90 mg q12 ER Morphine to IV

hydromorphone as continuous infusion 24-hr Morphine dose = 180 mg po IV Morphine dose = 180/3 = 60 mg IV Morphine 60 mg IV = 60/10 X 1.5 = 9 mg

hydromorphone IV/24 hr Reduce dose 50% for cross-tolerance = 9/2 = 4.5

mg/24 hr = 0.2 mg/hr IV

Part One: Summary

Oral short-acting opioids are the mainstay of pain management for the majority of patients. They can be dose escalated as much as 50-100% per day because of rapid upregulation of receptors and short half-life. When dose requirements are high, long-acting opioids are more useful in controlling pain. Opioids are readily interconvertible according to established conversion ratios.

Opioids for PainPart Two

Opioids: Special ConsiderationsSublingual Morphine

Transdermal Fentanyl

Transmucosal Fentanyl

Methadone

Opioid Infusions

Opioid Side Effects: Delirium & Neurotoxicity

Sublingual Morphine

Advantage: Longer duration of action (4 hr) vs. IV (1-2 hr) Disadvantages: 1. Data do not support more rapid absorption through

sublingual mucosa than by oral route 2. Mean time to maximum concentration is shorter with PO than

with SL morphine Bioavailability of SL morphine is only 9% vs. 23.8% with an oral

solution Absorption through oral mucosa is best with potent, non-

ionized and lipid soluble drugs. SL morphine has low potency, is highly ionized and one of the least lipid soluble opioids, making it a poor choice as a SL med.

Fentanyl Dose Conversions

Mr. L is an 80 year-old man with cancer who has been on a morphine drip in the hospital at 3 mg/hr. Upon discharge back to the nursing home the drip is dc’d and he is placed on a 50mcg/hr Fentanyl patch. The next day he is found in pain, nauseous, jittery and diaphoretic. What happened to Mr. L?

Dosage Conversion: Oral Morphine to Transdermal Fentanyl

PO MorphineTransdermal fentanyl (mg/24 hr) (mcg/hr) 45-134 25 135-224 50 225-314 75 315-404 100 1035-1124 300

– Source: Janssen Pharmaceutica

Dosage Conversion: Oral Morphine to Transdermal Fentanyl

Mcg/hr dose of Duragesic = ½ X mg/day dose of oral morphine

Example:– Duragesic 100 mcg/hr dose Q72 hrs = Oral Morphine SA

100 mg Q12 hrs or– Duragesic 2400 mcg or 2.4 mg/day = MS 200 mg/day (ratio

1:80)

– Levy, MH. Pain Management Center, Fox Chase Cancer Center at NHO Annual Meeting, Oct., 1992

Fentanyl Conversion-2

In PDR, conversion of morphine to fentanyl is 135-224 mg of morphine = 50 mcg/hr fentanyl patch. The patient was receiving 3 X 24 = 72 mg IV morphine X 3 = 216 mg oral morphine/24 hrs. So, according to PDR, the appropriate conversion dose is 50 mcg/hr fentanyl.

Fentanyl Conversion-3

An Alternate Formula, published by Breitbart et al (2000) uses a fixed dose conversion ratio:

2 mg oral morphine = 1 mcg/hr transdermal fentanyl

So 216 mg oral morphine is approximately equianalgesic to 100 mcg/hr fentanyl

So the patient was underdosed on discharge from the hospital, so was in pain

Fentanyl Conversion-4

Therapeutic blood levels of fentanyl are not reached for 13-24 hours after patch is applied.

So the patient was having withdrawal symptoms. Other breakthrough meds should have been used until the fentanyl had reached therapeutic levels.

Note also: Drug will continue to be released into the blood for at least 24 hrs after patch removal, so when replacing the patch, the new drug should be titrated up accordingly.

Upward titrations of fentanyl should be done no more often than every 48-72 hours.

Oral Transmucosal Fentanyl Citrate

OTFC- a solid formulation of fentanyl, a lozenge on a handle

Lipid soluble and 80% non-ionized, so very suitable for transmucosal absorption

Bioavailability higher if absorbed through oral mucosa than if swallowed

Rapid onset of analgesia (3-5 min), with peak effect at 20-40 minutes, short half-life

OTFC-2

Available in 200, 400, 600, 800, 1200 & 1600 mcg dosage strengths

Place between cheek and gum, move gently side to side for 15 min.

Always start at 200 mcg and titrate up If first dose inadequate, take a second dose 30 min

later. If that is effective, switch to 400 mcg doses. Pt should take no more than two units per pain

period during initial titration period.

Methadone for Pain: Why?

Acts as both a mu receptor agonist and an NMDA receptor antagonist. Its NMDA action makes it very useful in the treatment of neuropathic pain.

Methadone is sometimes effective for refractory pain when morphine or hydromorphone are not.

A special license to prescribe methadone is not required, except for those treating addiction.

Methadone: Unique Qualities

Has an extended half-life, up to 190 hours, yet duration of analgesia is 6-12 hours after steady state is achieved.

Rapid titration guidelines do not apply to methadone. Dose should not be increased more frequently than every 5-7 days. It is not indicated in poorly controlled pain where rapid dose adjustments are needed.

Patients with a prolonged QT interval, or who have other risk factors for Torsades, may need EKG monitoring.

Starting Methadone

After a single dose, there is a short distribution phase (with acute pain relief) with a half-life of 2-3 hrs and a slow elimination phase (half-life 15-60 hrs).

Dosing must account for accumulation of the drug over days.

No dose reduction is required with renal failure. Drug interactions: Rifampin, phenytoin,

carbamazepine, and several antiretroviral meds decrease methadone levels. Amitriptyline, fluconazole, erythromycin, metronidazole, fluoxetine and grapefruit juice increase levels.

Starting-2

1. Begin methadone 5 or 10 mg po bid or tid for 5-7 days. With elderly, begin at 2.5 mg QD/BID and titrate up more slowly.

2. If pain persists, increase dose by 50%, continue for 5-7 days, and increase dose every 5-7 days until pain controlled.

3. Use short-acting opioid with short half-life (e.g. morphine 10 mg) every 1-2 hrs prn for breakthrough pain and to provide relief during titration phase.

Conversion to Methadone

Conversion Ratio of oral Morphine to oral Methadone3:1, 3mg morphine to 1 mg methadonefor doses of morphine up to 100 mg/day101-300 mg – 5:1301-600 mg – 10:1601-800 mg – 12:1801-1000 mg – 15:1>1001 mg – 20:1

Conversion to Methadone-2

Calculate equianalgesic dose of methadone from total current opioid dose.

Day 1: Replace 1/3 of opioid dose with oral methadone on bid or tid schedule.

Day 2: Replace next 1/3 of opioid dose. Day 3: Complete change to methadone. Reference: J Pall Med 2002; 5:127-138.

Opioid Infusions in the Imminently Dying Patient

1. Calculate an equianalgesic dose of currently used opioids. E.g. 60 mg q12 po = 120 mg/24 hr = 40 mg IV/24 hr = 2 mg/hr basal rate

2. If the current opioid dose is ineffective, escalate the basal dose by 25-100%

3. Give a loading dose when starting the infusion if equianalgesic dose is being escalated or if pt is opioid naïve (4-10 mg loading dose prior to starting 2 mg/hr infusion)

4. Choose a bolus rescue or PCA dose. A dose 50-150% of the hourly rate is a place to start. In this example, bolus at 1-3 mg.

Opioid Infusions-2

5. Choose a dosing interval. Peak effect from an IV bolus is 5-10 min, so dosing interval should be 10-20 min.

6. Reassess for desired effect vs. side effects every 10-15 min. until stable. Adjust bolus dose every 30-60 min. until desired effect is achieved.

7. Reassess need for a change in basal rate no sooner than every 6-8 hrs. Take total bolus doses into account, but never increase basal rate by more than 100% at one time. Be sure to give a loading dose to rapidly achieve steady-state blood levels.

When pts become anuric close to death, d/c continuous dosing in favor of bolus dosing to prevent metabolite accumulation and delirium.

Opioid Infusion Titration Orders

Bad example: MS 2-10 mg/hr, titrate to pain relief Places full responsibility for dose titration on the nurse Provides no guidance re: how fast to titrate (q hr, q shift?) or dose

titration intervals (should the dose be raised from 2 to 3 mg or 2 to 10 mg?)

Sets up potential for overdosage by too zealous dose escalation Provides only one option for poorly controlled pain—increasing basal

rate Makes no sense to dose escalate more frequently than every 8 hrs,

since it takes that long to achieve steady-state blood levels after a basal dose change

Preferred: MS 2 mg/hr and MS 2 mg q15 min prn breakthrough pain (or 2 mg via PCA dose) and RN may dose escalate the prn dose to a maximum of 4 mg within 30 minutes for poorly controlled pain.

Opioid Side Effects: Delirium

Occurs in as many as 80% of inpatients on opioids; often goes undiagnosed and untreated.

Manifests as confusion or hallucinations Risk is highest in late-stage or actively dying

cancer pts who have become dehydrated and whose renal clearance is compromised.

Delirium: Treatment

Fluids to correct dehydration You may try decreasing opioid dose, but not

at the expense of pain control. A better way is to switch to an equianalgesic

dose of a different opioid. Use antipsychotics such as haldol or

chlorpromazine. Avoid benzodiazepines, as pts may have a paradoxical reaction.

Opioid Side Effects: Myoclonus and Neurotoxicity

More risk as pt gets closer to death Manifests as muscle twitching or

psychomotor agitation May try reducing opioid dose, but not at

expense of pain control Opioid switch Benzodiazepines such as lorazepam or

clonazepam can be effective.

Opioid Toxicity

Occurs as opioid dose is increased in response to perception that pt is still in pain

If myoclonus occurs, the appropriate opioid dose has been exceeded.

Or toxicity presents as generalized, rather than localized, pain—the opioid overwhelms the CNS

Opioid Toxicity: Treatment

DO NOT increase opioid dose, even though the pt has generalized pain.

Try a reduction in dosage of 25%. If this is effective you may further reduce the dose until symptoms are resolved.

If pain increases on the lesser dose, either restore the previous dose and add benzos or switch to an equianalgesic dose of a different opioid.

Part Two- Summary

Sublingual morphine, while easy to use, appears to have less effectiveness than oral forms. Transmucosal fentanyl, though more expensive, can provide long-term pain relief.

Transdermal fentanyl is helpful for patients with chronic pain who cannot tolerate oral medication with its side effects, but is not useful for acute or uncontrolled pain.

Methadone is cheap and particularly useful for neuropathic pain. It must be used cautiously with respect to its long half-life.

Summary (cont.)

Opioid infusions, both IV and subcutaneous, are very useful for hospitalized patients with severe pain, as well as for patients who are imminently dying.

Delirium and neurotoxicity are common side effects of opioids, and can be treated with dose reduction, opioid switching, and administration of IV fluids and antipsychotics (delirium) or benzodiazepines (myoclonus).