Opioid Analgesics and Antagonists

Ed Bilsky, Ph.D.Department of PharmacologyUniversity of New England

Phone 207.602.2707

E-mail: ebilsky@une.edu

Case 1A 33-year-old truck driver presented with left shoulder pain dating from a motor vehicle accident 4 years before. His pain was described as “constant” and “constricting,” with “stabbing electric, shock-like” characteristics. It had increased over the past 2 years to intensities between 7 and 10 out of 10 (0 = no pain, 10 = excruciating pain). He had undergone excision of the lateral end of the left clavicle and rotator cuff decompression 3 years earlier, receiving physiotherapy before and after surgery. He had also used heat and a machine providing transcutaneous electric nerve stimulation and had received intra-articular injections of anaesthetic agents and steroids. When first seen in the pain clinic he was taking, on average, one tablet of acetaminophen/codeine/ caffeine (300 mg/30 mg/15 mg) and one tablet of acetaminophen/oxycodone (325 mg/5 mg) 5 times daily. He also drank 10 cups of coffee daily, had been unable to sleep more than 3 hours in 24 for the last 2 years and was working night shifts. Apart from smoking a pack of cigarettes per day, the patient had no other risk factors for addiction, and he described having a supportive wife and 2 daughters. What modifications to his medication regimen and lifestyle might provide him with better pain management?

Opium and Opioids: A Brief History

• Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and efficacious as opium… Sydenham, 1680

• Opium has been used and abused for thousands of years– the antidiarrheal actions were used to treat dysentery

Opium and Opioids: A Brief History

• In 1806, Sertürner isolated an alkaloid from opium which he called morphine (L. morpheus, god of dreams)– ushered in the field of alkaloid medicinal chemistry

• A number of other alkaloids were subsequently isolated from opium– codeine, papaverine, thebaine, etc.

Opium and Opioids: A Brief History

• Problems with opioid addiction were recognized early on– development of hypodermic syringe/needle - Soldier’s disease– patent medicines

• There has been a long history of trying to modify the chemical structure of morphine to decrease side-effects– heroin as a nonaddictive alternative to morphine!!!– synthetic agents such as methadone– mixed opioid agonists/antagonists

• The field of opioid pharmacology has also been the source of major advances in scientific methodology and medicinal chemistry– development of radioligand binding assays in the early 1970s and the

identification of opioid receptors– isolation of endogenous opioid peptides in 1975– cloning of all three opioid receptors in the early 1990s

Opioid Receptors

• Currently, there are three cloned opioid receptors– mu, delta and kappa

• Each receptor type has similarities and key differences with regard to the others– members of the G-protein coupled receptor family– tend to produce inhibitory effects on

neurotransmission– distinct distributions in the CNS

• Most of the currently available opioids work through the mu opioid receptor

Mechanism of Action-Cellular

• Opioid receptors are coupled to the Gi/Go class of G-protein coupled receptors

• Opioid agonist administration leads to an inhibition of adenylyl cyclase and a decrease in cAMP formation

• The downstream mediators of the opioid response include an opening of inwardly rectifying K+ channels and an inhibition of voltage-gated Ca2+ channels

G-Protein Coupled Receptors

Mechanism of Action-Systems

Opioid analgesics can work at several levels:

• Peripheral receptors– role in inflammatory pain states and hyperalgesia

• Spinal cord– profound analgesia/anesthesia with spinal

administration

• Supraspinal sites– activation of descending pain control pathways– involvement of the limbic system

Peripheral Sites of Action

Peripheral Sites of Action

Fig. 1. Columns represent differences (mean ± SEM) in VAS scores (VAS) of patients receiving saline versus patients receiving morphine(VASsal - VASmor) in trial 1 (A), trial 2 (B), and trial 3 (C). In patients with inflammatory tooth pain (A), differences in VAS scores between the saline and morphine group are significantly different (P < 0.05, RM-ANOVA). In patients without inflammatory tooth pain (B) or with perineural morphine administration (C) differences in VAS scores are not significantly different

Likar R, Koppert W, Blatnig H, Chiari F, Sittl R, Stein C, Schafer M. Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 2001 Apr;21(4):330-7

Inflammatory tooth pain

No inflammatory tooth pain

Perineural morphine

Spinal Analgesia

• Opioid receptors are located on the primary afferent terminal– attenuates release of

substance P and glutamate

• High concentrations of opioid receptors are also seen postsynaptically in laminae I, II, V and X of the spinal cord– activation increases potassium

conductance, thereby hyperpolarizing second order neurons

– decreased GABA release

www.hosppract.com/issues/2000/07/brook.htm

Supraspinal Analgesia

• Brainstem circuits may inhibit rostral movement of nociceptive information and activate descending pathways that alter nociceptive processing in the spinal cord– periaqueductal gray– rostral ventral medulla

• Parts of the limbic system activated by opioids may alter the emotional response to painful stimuli– nucleus accumbens/ventral forebrain

Endogenous Opioids

• There are at least three families of endogenous opioid peptides– individual peptides derived from larger precursors

• Each family has a unique anatomical distribution and pharmacological profile

Endogenous Opioids

• The precise role that these peptides play in the regulation of physiological functions is unclear– pain transmission– mood– eating/drinking behaviors– and many others

Stimulation of Central Sites Produces Analgesia in Humans

Electrical Stimulation of PAG

Beta-endorphin Surrounds PAG

Hosobuchi et al, 1977 A. Basbaum

Mammalian Endogenous Opioid Peptides

Precursor Endogenous peptide Amino acid sequence

Pro-opiomelanocortin-Endorphin YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE

Pro-enkephalin [Met]enkephalin YGGFM[Leu]enkephalin YGGFL

YGGFMRFYGGFMRGL

Metorphamide YGGFMRRV-NH2

Pro-dynorphin Dynorphin A YGGFLRRIRPKLKWDNQDynorphin A(1-8) YGGFLRRI Dynorphin B YGGFLRRQFKVVT-neoendorphin YGGFLRKYPK

-neoendorphin YGGFLRKYP

Pro-nociceptin / OFQ Nociceptin FGGFTGARKSARKLANQ

Pro-endomorphin* Endomorphin-1 YPWF-NH2

Endomorphin-2 YPFF-NH2

*Presumed to exist, awaiting discovery

Main Effects of Opioids at Therapeutic Doses

Desirable Undesirable Mixed Desirability

Analgesia Nausea, vomiting Sedation

Relief of anxiety Urinary retention Euphoria

Dysphoria Cough suppression

Mental clouding Bowel motility

Tolerance

Drug dependence syndrome

Respiratory depression

Postoperative ileus

Biliary spasm

Analgesic Effects

• Pain is a complex phenomenon that has both sensory and emotional components

• Opioid analgesics can inhibit both the transmission of the sensory signals to higher CNS centers and the affective aspects of the experience

• Many patients report that they feel the pain, yet it is not necessarily aversive

• The higher efficacy compounds have a broad spectrum of activity

Tolerance

• Tolerance refers to the phenomenon in which previous exposure to a drug results in a diminution of an effect or the need for a higher dose to maintain an effect

• Tolerance to opioid analgesics has been reported in both animal models and clinical situations

• Tolerance to the adverse effects of opioids may also occur, though the rate and degree of tolerance varies for each effect and each patient

Mechanisms of Tolerance

• There have been a number of hypotheses put forward to explain the development of tolerance– receptor down regulation– receptor internalization– receptor/G-protein desensitization– other compensatory adaptations

• My laboratory, and others, are trying to develop opioid analgesics that produce less tolerance, or adjunct agents that limit the development of tolerance

Naive Tolerant

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Models of Tolerance

Log Dose (mg/kg)

3

Management of Tolerance

• The development of tolerance can usually be managed effectively by:– considering a differential diagnosis for the loss of

analgesia (e.g., progression of disease)– increasing the dose of opioid analgesic– switching to another opioid analgesic with greater

efficacy– adding alternative pain management strategies

Physical Dependence

• Prolonged exposure to an opioid agonist can produce adaptations at the cellular and systems levels which oppose the drug effect– the patient has become physically dependent on

the drug– physical dependence does not equal

addiction!!!

• The discontinuation or sudden reduction in drug levels, or the administration of an antagonist, can lead to a withdrawal syndrome

Symptoms and Signs of Opioid Withdrawal

Symptoms Signs

restlessness pupillary dilation

irritability sweating

increased sensitivity to pain tachycardia

nausea vomiting

abdominal cramps diarrhea

myalgia hypertension

dysphoria yawning

insominia fever

anxiety rhinorrhea

drug craving piloerection

Physical Dependence

• Overt opioid withdrawal symptoms can usually be managed effectively:– reinstatement of a low dose of the opioid– gradual tapering of opioid agonist– use of adjunct agents to ease withdrawal symptoms

(e.g., clonidine)

• Subtle episodic withdrawal symptoms may, however, complicate pain management– use of longer acting agents over short acting

opioids

• Fear of Addiction

"When we surveyed the parents of children dying with cancer, we asked them what the major concern was about their child receiving narcotics. It was that 'my child will grow up to be an addict,' and these were clearly children that were going to die."

Kathleen Foley, M.D.

(Dahl et al., 1986)

Barriers to Adequate Pain Control

PAINKILLER TEARS THROUGH MAINE OxyContin Addicts, Crime Wave Linked

LEWISTON, Maine - The crowbar rained on Dorothy Treadwell.  Once.  Twice.  Twenty times.  The tiny orange pills her assailant sought scattered to the ground.

Treadwell, 48, struggled to rise.  She gripped a radiator.  Again came the crowbar.  The blow left her pinky hanging by a scrap of tendon.  She ran bloodied into the street. Her neighborhood by the railroad tracks near downtown here is a poor collection of rickety wood houses aside metal silos of small-time factories.  But such savagery is rare. 

The assailant, said Treadwell, was Cleve Herrick, her live-in lover.  He is a raging OxyContin addict, she said, desperate - like hundreds of others in Maine - to obtain the addictive prescription painkiller, often called “poor man's heroin.” “It was pretty bad for this area.  I mean, a crowbar?” recalled James Theiss, a Lewiston police detective on the case in which Herrick is now charged with two counts of aggravated assault.

OxyContin, a remarkably effective painkiller, is shredding the social fabric of parts of Maine, creating a Wild West-like anarchy in many communities, according to dozens of interviews with state officials, doctors, and police.

If you have been prescribed OxyContin, you may be entitled to compensation

Please review the information on our site and contact us for immediate legal assistance.

OxyContin, marketed by Purdue Pharma L.P., has been linked to addiction, suffering and death of patients using this prescription painkiller.

OxyContin, approved by the FDA in 1995, is a time-released form of oxycodone, an opium derivative, which is the same active ingredient in Percodan and Percocet. OxyContin is intended for use by terminal cancer patients and chronic pain sufferers. It has been linked to at least 120 overdose deaths nationwide.

It has been alleged that Purdue Pharma L.P. has marketed the drug excessively without stressing its addictive nature. Doctors and pharmacists say the manufacturer of OxyContin promoted the benefits of the drug without providing enough warning about the serious side effects of addiction. It has also been alleged Purdue Pharma L.P. made misrepresentations and failed to sufficiently warn individuals regarding appropriate use and risks of OxyContin.

It has been reported that OxyContin's sales exceeded $1 billion in the U.S. in 2000.

Addiction Liability

• Studies in the 1920s and 1950s were influential in setting opioid analgesia policy in the later part of the 20th century– chronic opioid therapy leads to addiction– Kathleen Foley quote

• These studies had methodological flaws and more recent reports have suggested that the risk of iatrogenic opioid addiction is very low– the incidence of addiction in chronic pain patients

parallels the lifetime prevalence rates in the general population (Fishbain et al., 1992)

Respiratory Depression

• Respiratory depression is the most life-threatening of the side-effects associated with opioid analgesics– major cause of fatal opioid overdoses

• Opioid receptors are located on chemoreceptors and ventral respiratory group neurons in the medulla– diminished sensitivity to changes in O2 and CO2

levels– changes in tidal volume and frequency of

respiration

Respiratory Depression

• Respiratory depression is typically not a problem if guidelines are followed– more common with bolus dosing in naïve individuals– some of the fentanyl analogues can produce chest

wall rigidity which interferes with the muscles of breathing

– partial agonists typically produce less depression

• Special clinical populations include patients with asthma, emphysema, COPD, cor pulmonale and increased intracranial pressure– naloxone can reverse the depressant effects of

most opioids

Effects on Mood/Cognition

• Analgesic doses of most opioids produces relief from anxiety and a floating, dream-like state– majority of people report euphoric feelings, though some

patients find the experience dysphoric– kappa opioid agonists appear to produce dysphoria

• Drowsiness and clouding of mentation are frequently reported effects of opioids– elderly more susceptible to these effects

• Chronic use of opioids results in little, if any, impairment of cognition or motor skills (e.g., driving skills)

Nausea and Vomiting

• Opioids stimulate the chemoreceptor trigger zone producing nausea and vomiting– tolerance typically occurs to repeated dosing

• Ambulation exacerbates the nausea and vomiting

• Administration of antiemetic drugs can decrease these side-effects

• Orthostatic hypotension is also possible with analgesic doses of opioids

Constipation

• One of the biggest concerns with chronic opioid administration is severe constipation– occurs in almost all patients receiving chronic

opioids

• In many cases, constipation is the primary reason for the patient discontinuing opioid therapy

• Constipation can be partially managed by using laxatives– development of opioid antagonists that do not cross

the blood-brain barrier

Antitussive Effects

• Opioid analgesics can strongly suppress the cough reflex– exact mechanisms are unknown

• Weaker opioids such as codeine are formulated for this purpose– accumulation of secretions in the lungs can lead to

airway obstruction

• Many OTC cough suppressants contain the opioid-like molecule dextromethorphan– decreased side-effects compared to codeine

Cardiovascular Effects

• Most opioids have no significant direct effect on the heart– morphine is the drug of choice for relieving pain

from cardiac ischemia– possible cardioprotective effects in ischemic models

• Hypotension may occur following opioid administration– histamine release and depressant effects in the

vasomotor systems of the brainstem

Other Opioid Effects

• Constriction of biliary smooth muscle, resulting in biliary colic

• Renal function is depressed– antidiuretic effect mediated through mu receptors– increased sphincter tone may produce urinary retention

• Prolongation of labor– Morphine versus meperidine

• Flushing of the skin, sweating and itching

• Modulation of immune function

Drug Interactions

• Many other CNS depressants can act in an additive or synergistic manner with opioid analgesics– benzodiazepines– barbiturates– alcohol– antipsychotics

• MAO inhibitors with opioids may produce hyperpyrexic coma and hypertension– especially with meperidine

• Stimulants have sometimes been used to counteract the CNS depressant effects of opioids

Pain Management Techniques

PharmacotherapyNon-Pharmacological Treatments

Physical therapy Procedures

Opioids Acupuncture Active exercise Trigger point injections

Nonsteroidals Relaxation Passive exercises Nerve blocks

Muscle relaxants Visualization Pool therapy Epidural steroids

Benzodiazepines Prayer TENS unit Intrathecal opioids

Antidepressants Pain groups Massage therapy Spinal cord stimulation

Antianxiety agents Chiropractic

Antiarrhythmics Ice/heat

Antiseizure agents Bed rest

Pain Management Techniques

Full Efficacy Agonists

Moderate/Weak Efficacy Agonists

Mixed Acting Agonists/Antagonists

Misc. Compounds

Morphine Hydrocodone Buprenorphine Tramadol

Methadone Oxycodone Butorphanol

Hydromorphone Meperidine Pentazocine Naloxone

Oxymorphone Codeine Nalbuphine Naltrexone

Levorphanol Propoxyphene Nalmefene

Fentanyl Diphenoxylate

Remifentail Loperamide

Choosing an Appropriate Opioid

• Assessment of the pain– severity and type of pain

• Pharmacokinetic considerations– route of administration– duration of action

• Pharmacodynamic considerations– differences between drugs, novel effects

• Individual patient factors– age, sex, genetic factors– disease states (renal or liver disease)– concurrent drug therapy– psychosocial factors

WHO Analgesic Ladder

Morphine

• Prototypical mu opioid agonist– indicated for moderate to severe pain

• Multiple preparations available– parenteral– oral and sustained release (MS Contin)– rectal

• M3ß- and M6ß-glucoronides are primary metabolites– may contribute to analgesic effects (M6ß) and side-effects (M3ß)– lower dosing in geriatric patients (smaller Vd and renal function)

• Morphine produces histamine release– bronchoconstriction and vasodilation– patients with reduced blood volume are more sensitive to the

vasodilatory effects of morphine

Codeine

• Codeine is a weak opioid analgesic– has limited affinity for opioid receptors– considered a prodrug

• Needs to be demethylated to morphine– approximately 10% of Caucasians lack the

cytochrome P450 isozyme (CYP 2D6)– these patients will get no relief from even high

doses of codeine

Methadone

• Full opioid agonist– efficacy similar to morphine– good oral bioavailability– long half-life and duration of action

• The compound has antagonist actions at the NMDA receptor complex– decreased development of tolerance and physical

dependence?– role in treatment of neuropathic pain?

• Used in the treatment of heroin addiction and managing opioid withdrawal

Fentanyl and Analogues

• Relatively selective mu opioid agonists– typically more potent than morphine– shorter duration of action (e.g., remifentanil)– high efficacy compounds

• Fentanyl can be given by various routes– transdermal patch– fentanyl lozenge (lollipop)

• Muscular rigidity more pronounced with this class of compounds compared to morphine

Meperidine

• Moderate efficacy opioid agonist– used for moderate pain

• The compound has antimuscarinic effects– cardiovascular effects possible– limited constriction of the pupil

• Accumulation of normeperidine(metabolite) can produce seizures– caution with high doses and in patients with renal insufficiency– No longer recommended for chronic pain management– Do not use with MAO inhibitors (serotonin syndrome)

• Other notes– Applications in labor and delivery???– decreased urinary retention and constipation versus morphine???– used to treat post-anesthetic shivering

Oxycodone

• Opioid agonist with moderate efficacy

• Recent controversy with this drug– sustained release preparation-OxyContin– pellets can be crushed and a solution injected

• Purdue Pharma has tried to reformulate the compound with naloxone– oral administration would still be effective– parenteral administration would result in blockade

of opioid actions

Propoxyphene

• Very weak opioid agonist– analgesic effect equivalent to aspirin

when used alone– typically administered in combination

with aspirin and acetaminophen

• Limited clinical utility– concern with accumulation of

norpropoxyphne (metabolite) --> convulsions, hallucinations and cardiotoxicity possible

– Irritating to tissues when injected

Diphenoxylate/Loperamide

• Diphenoxylate is a weak opioid agonist with low abuse liability– atropine added as a combination product for

treatment of diarrhea and to discourage abuse

• Loperamide is a moderate efficacy opioid agonist that does not readily cross the blood-brain barrier– low abuse liability– common OTC antidiarrheal medication

Mixed Opioid Agonists/Antagonists

• These compounds are characterized by different actions on each of the opioid receptors– nalbuphine-kappa agonist/mu antagonist– buprenorphine-partial mu agonist– pentazocine-kappa agonist, weak mu agonist

• These agents are contraindicated in opioid dependent patients– severe withdrawal syndrome may develop

Tramadol

• Novel analgesic action– weak mu opioid agonist– blocks reuptake of serotonin– blocks reuptake of norepinephrine

• Marketed as a compound with efficacy similar to codeine with less side-effects– no addiction liability?– less GI effects– efficacy in neuropathic pain states1

– expensive

1Cochrane Database Syst Rev. 2004;(2):CD003726

Naloxone

• Prototypical opioid antagonist

• Used to treat opioid overdose– low oral bioavailability– short duration of action

• Will precipitate a severe withdrawal syndrome in opioid dependent patients

• New evidence suggests that this compound has inverse agonist actions in opioid dependent states– increase in withdrawal symptoms

• Prototypical opioid antagonist

• Used to treat heroin addicts– good oral bioavailability– long duration of action

• New evidence suggests that this compound has inverse agonist actions in opioid dependent states– role in patient compliance?

• Approved for the treatment of alcoholism– decreases binge type drinking

Naltrexone

QuickTime™ and a decompressor

are needed to see this picture.

• First in class peripheral opioid antagonist– Quaternary nitrogen prevents BBB transport– Must be given by s.c. injection

• Indicated for opioid-induced constipation in patients with advanced illness and who are not responding to conventional laxative therapy– Can produce severe diarrhea and abdominal

cramping, especially in opioid dependent patients– Contraindication of mechanical bowel obstruction

Methylnaltrexone

1. Analgesia should be integrated into a comprehensive patient evaluation and management plan

2. The emotional and cognitive aspects of pain must be recognized and treated

3. There is no reliable way to objectively measure pain

4. Pain is most often under-treated, not over-treated

5. Beware of the “squeaky-wheel-gets-the-oil” phenomenon of pain control

6. Pain control must be individualized

7. Anticipate rather than react to pain

8. Whenever possible, let the patient control his or her own pain

9. Pain control is often best achieved by combination therapy

10. Pain control requires a multidisciplinary team approach

Principles of Pain Control