section name header

Info


A. Endogenous Opioid Peptides navigator

  1. Three Classical Families
    1. Enkephalins
    2. Endorphins
    3. Dynorphins
  2. Novel Endogenous Opioid Related Peptides
    1. Orphanin FQ / Nociceptin
    2. Endomorphin 1
    3. Endomorphin 2
  3. Endorphins
    1. Major opioid peptide is ß-endorphin
    2. Derived from proopiomelanocortin (POMC)
    3. Bind primarily mu and delta opioid receptors
  4. Enkephalins
    1. Derived from proenkephalin
    2. Leu5-enkephalin and Met5-enkephalin
    3. Bind delta somewhat better than mu receptors
  5. Dynorphins
    1. Derived from prodynorphin
    2. Dynorphin A binds kappa somewhat better than mu receptors
    3. Dynorphin B and alpha-neoendorphin bind kappa much better than mu or delta

B. Opioid Receptorsnavigator

  1. Three Classical Receptor Families
    1. Mu
    2. Delta
    3. Kappa
  2. Recently discovered N/OFQ receptor
  3. All receptors are G-protein coupled (7 transmembrane domain) receptors
    1. All are coupled to inhibitory G proteins which reduce adenylate cyclase activity
    2. Also activate potassium currents
    3. Suppress voltage gated calcium currents
  4. All classical receptors are associated with supraspinal and spinal analgesia
  5. Other Effects of Classical Receptors
    1. Respiratory: mu agonists cause respiratory depression
    2. Gastrointestinal Tract Transit: mu and kappa reduce transit
    3. Sedation: mu and kappa agonists increase
    4. Prolactin and Growth Hormone Release: mu (some delta) increase
    5. Feeding: all receptors increase; antagonists reduce
    6. Diuresis: kappa increases
  6. Tolerance [2]
    1. Defined as decrease in effectiveness of a drug with repeated administration
    2. Acute and chronic tolerance to opioids are well described
    3. Acute tolerance to opioids likely due to phosphorylation of mu and delta receptors
    4. Chronic tolerance to opioids may be due to altered intracellular trafficking
    5. Novel opioid ligands with less alteration of trafficking are undergoing study

C. Classes of Opioid Agentsnavigator

  1. Analgesics
    1. Primarily mu receptor agonists
    2. Mixed mu agonist-antagonists do not have reduced side effects at equipotent doses
    3. Partial mu agonists have similar effects as mixed agonist-antagonists
    4. Parenteral delta receptor agonists (peptides) may also have analgesic effects
    5. Kappa receptor agonists in animals act on spinal neurons and have analgesic effects
  2. Reversal of Opiate Effects
    1. Opioid antagonists primarily used in opiate overdoses
    2. May also be useful in shock or other forms of stress
  3. Centrally active antitussive (anti-cough) agents
    1. Dextromethorphan - D-isomer of codeine analog methorphan (not analgesic or addictive)
    2. Codeine - also has good antitussive activity
  4. Antidiarrheal Agents
    1. Diphenoxylate - in combination with atropine, branded Lomotil®
    2. Loperamide (Imodium®, others) - probably interacts with gastrointestinal opioid receptors

D. Opioid Analgesics [2,3] navigator

  1. Opioid agonists are used primarily for anesthetic properties
  2. Mainly work centrally through mu receptor agonism
    1. Central activities result in drowsiness, respiratory and cardiovascular depression
    2. Peripheral opiate receptors involved in pain sensation have been characterized
    3. Peripherally acting agents without central effects are under development
  3. Equianalgesic doses of opiates are attainable for most of the agents, whether they belong to the less potent or more potent groups
  4. Most patients with chronic pain not associated with terminal illness can achieve good pain control with a stable dose of opioids with minimal addiction risk [2]
  5. Mainstay of treatment of cancer pain
  6. Neuropathic Pain
    1. Intravenous fentanyl has effects on neuropathic (and cancer) pain, independent of its sedative properties
    2. There are no clinical characteristics of neuropathic pain which predict opiate responses
    3. Responses in neuropathic pain are suboptimal with considerable side effects
  7. Side Effects
    1. Respiratory suppression is the most concerning side effect
    2. There is very little addiction potential in patients with chronic pain taking opiates
    3. Constipation is a major side effect
    4. Stool softeners and/or laxatives should be given with chronic opioids
    5. Failure to provide adequate laxative control can lead to ileus and impaction
    6. Chronic use of opiates for low back pain associated with substance abuse, addiction [17]
  8. All of these agents are controlled substances and most require written prescriptions in USA

E. Selected Opioid Agonists [2] navigator

  1. Equianalgesic Doses [4]
    1. Morphine: 10mg parenteral, 30-60mg oral
    2. Codeine: 120mg parenteral, 200mg oral
    3. Oxycodone: not available parenteral, 15-20mg oral
    4. Methadone: 10mg parenteral, 10-20mg oral (caution, can produce delayed sedation)
    5. Fentanyl: 0.1mg (100µg) parenteral, not available oral
    6. Hydromorphone: 1.5-2.0mg parenteral, 6-8mg oral
    7. Oxymorphone: 1mg parenteral (Numorphan®), 1mg oral (Opana®, Opana® ER)
    8. Meperidine: 75-100mg parenteral, 300mg oral (caution, metabolite can cause seizures)
  2. More Potent Agents
    1. Meperidine (Demerol®): iv, im (with Vistaril®), or po; 50-100mg, 2-4 hour im duration
    2. Caution with meperidine, as metabolite can accumulate long term and cause seizures
    3. Fentanyl (Sublimaze®): short acting iv form with <1 hour duration after one dose
    4. Fentanyl Patch (Duragesic®): for chronic pain (usually cancer pain); patch over 72
    5. Morphine (various formulations, see below)
    6. Hydromorphone (Dilaudid®): initially 2-4mg po q4-6 hours; suppositories, injection also
    7. Hydromorphone ER (Palladone®): initially 12mg po once daily; titrate q2-3 days [15]
    8. Levorphanol (Levo-Dromoran®): 1.5-2.5mg im dose q3-6 hours; oral 2-4mg
  3. Less Potent Agents [5]
    1. Codeine - dose is 15-30mg po q3-6 hrs; high nausea rate, good cough suppressant
    2. Tylenol + Codeine - usually Tylenol #3; 1-2 tablets q4-6 hrs (prescription may be phoned)
    3. Oxycodone - 5-10mg po q4-6 hours or 10-80mg q12 hour. Better tolerated than codeine
    4. Oxycodone + Acetaminophen (Tylox®, Percocet®, Roxicet®) - 1-2 tablets q4-6 hours
    5. Oxycodone + Aspirin (Percodan®) - 5mg oxycodone + 325mg aspirin; 1-2 tabs q4-6 hours
    6. OxyContin® - controlled release oxycodone (10, 20, 40, 80mg q12 hours only)
    7. Hydrocodone + Acetaminophen (Vicodin®) - 1-2 tablets q4-6 hours (Rx may be phoned)
    8. Propoxyphene (Darvon®) - probably weaker than oxycodone
    9. Dihydrocodeine + ASA or acetaminophen (Synalgos-DC®, DHCplus®)
    10. Tramadol (Ultram®) - week mu receptor agonist, synthetic codeine analog, serotonin reuptake blocking activity; dose 50-100mg up to qid, maximum 400mg/day
  4. Morphine
    1. Relatively weak agent with slow onset
    2. Elimination half-life 1.7-3.3 hours of immediate release
    3. Elixir
    4. Immediate release (IR)
    5. Sustained release: MS Contin® (q12 hour), Avinza® (q24 hour)
  5. Fentanyl (Sublimaze®)
    1. About 100 fold more potent than morphine
    2. Active half life may be shorter than elimination time due to rapid exit from CNS
    3. Elimination half-life 3.1-6.6 hours
    4. Preferred over morphine due to less hypotension, no histamine release
  6. Sufentanil (Sufenta®)
    1. About 10 fold more potent than fentayl (1000X more than morphine)
    2. Usually more rapid anesthesia induction than fentanyl
    3. Little tendancy for accumulation, side effects
    4. Bradycardia is rare and responds to atropine
  7. Remifentanil (Ultiva®)
    1. About 250 fold more potent than morphine
    2. Elimination half-life 0.17-0.33 hours
    3. This agent has the most rapid elimination due to hydrolysis by serum esterases
    4. Mainly useful in short, painful procedures where rapid recovery is required
  8. Alfentanil (Alfenta®)
    1. About 10 fold more potent than morphine on a weight basis
    2. Very rapid onset of action
    3. Elimination half-life 1.4-1.5 hours
    4. Relatively wide disparity of responses between persons
  9. Methadone (Dolophine® and others) [6]
    1. Methadone is a long acting µ-opiate receptor agonist with less abuse potential than heroin
    2. Good pain relief, long acting opiate agonist with reduced withdrawal potential
    3. Dosing qid for pain relief (typically 5-10mg po qid)
    4. Addiction is much decreased compared with agonist agents
    5. Methadone prevents opiate withdrawal and reduces subjective effects of illegal opioids
    6. Duration of action (prevention of opiate desire) is 24-36 hours
    7. Initial dosage is usually 10-40mg/day in opiate dependent persons
    8. Doses >50mg/d are usually required initially to prevent cravings (and patient drop-out)
    9. Daily high dose (80-100mg) more effective than moderate (40-50mg) and low (20mg) methadone dose for opioid abstinance and completion of detoxification program [7]
    10. Reasonable choice for chronic intravenous drug abusers who need pain control
    11. This agent may still be abused
    12. Caution with chronic dosing for pain: can accumulate and cause increased sedation
    13. There is no maximum dose, and each patient needs to be titrated
    14. Urinalysis is usually done to monitor compliance and assess other illegal drug abuse
    15. Reduction rates are 10mg/week for >80mg/d, 5mg/wk for 40-80mg/d, and 2.5mg/wk for <40mg/d
  10. Levo-alpha-Acetylmethadol (LAAM) [7]
    1. Opioid agonist longer acting than methadone, may be used on alternate days (qod)
    2. LAAM is effective in a dose dependent fashion
    3. Recommended dose is 50/50/70mg or 100/100/140mg (thrice weekly)

F. Mixed Agonist/Antagonists navigator

  1. Butorphanol (Stadol®) [7]
    1. Available as im/iv and nasal spray (Stadol NS®)
    2. Mixed agonist/antagonist
    3. Moderate to severe pain
    4. Dose 1.5-2.5mg per spray
    5. Very expensive
  2. Buprenorphine (Buprenex®, Subutex®, Suboxone®) [8,9]
    1. Original formulation 0.4mg IM q3-6 hours (Buprenex®)
    2. Sublingual tablets approved for treatment of opioid dependence
    3. Mixed opiate agonist/antagonist (partial agonist at mu receptors)
    4. Clearly reduces opioid self-administration (opiate abuse)
    5. Dose is 12-16mg/day (usually begun at 2mg/day, dose doubled to 16-32mg/d)
    6. Can also be given as 8-24mg sublingually, daily or three times per week
    7. Maximum dose sublingual is 24-32mg daily
    8. Use in primary care setting is at least as effective as in drug-dependence centers
    9. As effective as high dose methadone and LAAM
    10. One year retention in buprenorphine group 100% versus 0% with placebo in Sweden [8]
    11. Schedule III agent (less severely restricted than methadone)
    12. Also available in combination with naloxone (Suboxone®) - currently available
    13. Suboxone® sublingual reduce opioid abuse administered in office-based setting [10]
    14. Suboxone® prescription guidelines at www.suboxone.com
  3. Pentazosine
    1. Talacen®: pentazosine 25mg with acetaminophen 650mg (1 tab q4 hours po)
    2. TalwinNx®: pentazosine 50mg with naloxone 0.5mg (to prevent IV abuse); 1-2 tab q4-6hr
    3. Indicated for moderate to severe pain, orally active
    4. Typical combination opiates with mild to moderate nausea potential
  4. Nalbuphine (Nubain® and others) - 12mg IM q3-6 hours
  5. Dezocine (Dalgan®) - 10mg im q3-6 hours
  6. Avoid mixed-agents in patients on pure agonists (may cause withdrawal)

G. Opioid Antagonistsnavigator

  1. For Narcotic Reversal
    1. Pure mu opiate receptor antagonists (see below)
    2. Naloxone (Narcan®)
    3. Nalmefene (Revex®)
    4. Acute, instantaneous reversal
    5. Short duration of action, usually shorter than opiate itself
    6. Opiate blockade may cause acute hypertension (acute "stress" response / withdrawal)
  2. Naloxone (Narcan®) [11]
    1. Pure opioid antagonist
    2. Drug half life ~30-45 minutes, given IV is the most commonly used agent
    3. Administered initially 2mg IV, repeat q2-3 minutes to 10mg total
    4. IV form is not appropriate for long term use
    5. Can also be given in q30 second bolus injections
    6. Now available in combination with buprenorphine sublingual (Suboxone®)
  3. Naltrexone (Depade®)
    1. Opiate antagonist also use for detoxification
    2. Patients are then usually converted to maintenance therapy on naltrexone
    3. Dose 50-100mg po daily or three times per week
  4. Nalmefene (Revex®) [12]
    1. Half life is significantly longer than naloxone
    2. Nalmefene may be used for higher dose opiate intoxication

H. Opiate Abuse [13,14] navigator

  1. Over 800,000 persons in USA with opioid dependence
  2. Diseases Associated with Opioid Abuse
    1. Overdose: anoxia, anoxic encephalopathy, coma and death
    2. Complications of needle sharing and unclean needles (see below)
    3. Heroin Nephropathy
    4. Spreading infectious disease, including tuberculosis (may be drug resistant)
  3. Classification of Opiate Associated Syndromes
    1. Acute Opiate Intoxication (Overdose)
    2. Chronic Opiate Intoxication (Chronic Abuse)
    3. Opiate Withdrawal Syndrome (voluntary or involuntary)
    4. Treatments for Opiate Dependence (Detoxification or Maintenance Therapy)
  4. Specific Agents
    1. Heroin: IV injection, snorted or smoked
    2. Morphine
    3. OxyContin: long acting oxycodone abused by crushing pill, snorted, dissolved for IV injection
    4. Hydrocodone abuse increasing as well
    5. Combination pentazocine (Talwin®) and tripelennamine (antihistamine)
    6. Other prescription agents may be abused: propoxyphene (Darvon®), meperidine (Demerol®)
    7. Methadone (Dolophine®) abuse now often reported
  5. Reccomendations for treating acute pain with opioids in patients on opioid agonists (drug abusers) have been made [16]
  6. National Institute on Drug Abuse Web Site: www.nida.nih.gov
  7. Substance Abuse and Mental Health Services Administration: www.dpt.samhsa.gov

References navigator

  1. Gutstein HB and Akil H. 2001. Pharmacol Basis Therapeut. 10th Edition. Page 569
  2. Ballantyne JC and Mao J. 2003. NEJM. 349(20):1943 abstract
  3. McQuay H. 1999. Lancet. 353(9171):2229 abstract
  4. Berde CB and Sethna NF. 2002. NEJM. 347(14):1094 abstract
  5. Oxycodone and OxyContin. 2001. Med Let. 43(1113):80 abstract
  6. Sees KL, Delucchi KL, Masson C, et al. 2000. JAMA. 283(10):1303 abstract
  7. Johnson RE, Chutuape MA, Strain EC, et al. 2000. NEJM. 343(18):1290 abstract
  8. Kakko J, Svanborg KD, Kreek MJ, Hellig M. 2003. Lancet. 361(9358):662 abstract
  9. Buprenorphine. 2003. Med Let. 45(1150):13 abstract
  10. Fudala PJ, Bridge TP, Herbert S, et al. 2003. NEJM. 349(10):949 abstract
  11. Naloxone (Narcan). 2002. 44:22
  12. Nalmefene. 1995. Med Let. 37(960):97 abstract
  13. Fiellin DA and O'Connor PG. 2002. NEJM. 347(11):817 abstract
  14. Cami J and Farre M. 2003. NEJM. 349(10):975 abstract
  15. Pallodone. 2005. Med Let. 47(1204):21 abstract
  16. Alford DP, Compton P, Samet JH. 2006. Ann Intern Med. 144(2):127 abstract
  17. Martell BA, O'Connor PG, Kerns RD, et al. 2007. Ann Intern Med. 146(2):116 abstract