BENZODIAZEPINES: TO PRESCRIBE OR NOT TO PRESCRIBE, THAT IS THE QUESTION! PHARMACOLOGY TYPES ACCUSE MEDIA OF "BENZO BASHING" Point out that BZ is great for treating GAD, and we don't (much anymore) withhold opiates for chronic pain just because of minor problems with addiction and withdrawal! Also point out that: In drug-naive animals and humans, BZs are NOT euphoric, hence extremely low abuse potential Dependency/withdrawal rare without chronic exposure (> 1 yr) to high doses This is the position taken by the text - "The original Pollyana attitude that the drugs can do no harm is no more accurate than irrational fears overstating benzodiazepines as dangerous drugs that do more harm than good" YET THEY ARE ABUSED! Two TYPES of abuse, recreational and iatrogenic Recreational - in 1988, 4.8% of US population reported EVER using tranqs recreationally, with a one-year prevalence of 2.2% and 1-month prevalence of 0.6% (1.3 million users/month) Recreational use is most common among hard- core drug users: + Heroin/methadone users inject BZ, get a heroin-like rush, use to increase effects of methadone + Speed freaks/crack addicts use to come down off a run DOSAGE is extremely high in such cases Iatrogenic dependence - users fear loss of "tranquility" PAIN AND ANALGESICS PERIPHERAL PAIN "RECEPTORS" NOCICEPTORS: Odd naked nerve endings in all parts of the body Using the peptide Substance P as a primary neurotransmitter Respond only to TISSUE DAMAGE When stimulated, SubP is released both in the spinal cord AND by the unmyelinated nerve endings TISSUE DAMAGE, INFLAMATION AND PAIN Tissue damage triggers a cascade of local events responsible for firing of nociceptive neurons Most involve release of chemical signals from damaged cells, signals which cause nociceptors to fire. These chemical messengers include: K+ Bradykinin, from damaged cells and blood vessels Histamine from specialized MAST cells Serotonin, from damaged cells and platelets Prostaglandins from damaged cells These substances cause nociceptors to fire, releasing SubP at the site of tissue damage SubP then causes further release of: Serotonin from platelets Bradykinin from blood vessels Histamine from mast cells PAIN TRACTS IN THE SPINAL COLUMN NOCICEPTORS PROJECT VIA SMALL-DIAMETER AXONS There are two types: C-fibers: smallest, unmyelinated fibers Aë-fibers: somewhat larger, myelinated Both synapse in the dorsal horn, outer layer, of the spinal cord Thus the relay neurons in the dorsal horn are the SECOND neuron in the pain system Or in the trigeminal nucleus of the brainstem for fibers from the head Then IMMEDIATELY cross the midline and ascend in the spinothalamic tract, laterally located in the white matter of the spinal cord PAIN IN THE BRAIN THERE ARE TWO PATHWAYS IN THE BRAIN: One, synapsing in the reticular formation and medial thalamus, mediates the affective (unpleasant) aspects of pain This system probably includes prefrontal cortex A second system goes to lateral thalamus and thence to somatosensory cortex, and is useful for LOCALIZATION of pain DESCENDING ENDOGENOUS ANALGESIC TRACTS THERE ARE NATURAL PAIN-CONTROL CIRCUITS MANY OF THESE FOCUS ON THE 2nd NEURON IN THE DORSAL HORN AND USE THE ENDOGENOUS OPIOIDS AS NEUROTRANSMITTERS Within the brain, there is an elaborate circuit involving: Pontine periacqueductal gray + a system which mediates fear and pain + Containing dense INHIBITORY opioid cells + Projecting to the median raphe Median raphe sends serotonin to excite opioid interneurons in the dorsal horn These opioid spinal interneurons inhibit pain transmission, presynaptically on SubP efferents and postsynaptically on the second- order neurons Large-diameter, sensory neurons from the periphery also can inhibit the spinal second-order neurons Probably accounting for immediate post-injury analgesia and acupuncture ANTIINFLAMMATORY ANALGESICS ASPIRIN IS THE PROTOTYPICAL DRUG IN THIS CLASS Often called "nonsteroidal" antiinflammatory drugs, or NSAIDS All NSAIDS inhibit cyclooxygenase (COX), the enzyme which synythesizes the prostaglandins (PG) There are two forms of COX: COX-1, found in stomach, kidneys and blood vessels COX-2, involved in inflammation ALL NSAIDS SHARE THREE PROPERTIES: Antipyretic: PG release in the hypothalamus triggers fever Antiinflammatory: PG plays an important role in inflammation Analgesic: Probably acting at the site of the wound, by blocking PG release which stimulates firing of nociceptors ALL NSAIDS SHARE SIMILAR SIDE EFFECTS: Stomach ulcers Blockade of platelet aggregation Inhibition of uterine motility (prolongs pregnancy) Inhibition of PG-mediated renal function (edema) Hypersensitivity reactions ASPIRIN Isolated from willow bark, synthesized by Bayer as salicylic acid in 1899 Name comes from SPIREA, a plant species from which salicylic acid was once derived Aspirin is an irreversible inhibitor of COX-1 and COX-2 Reyes syndrome is a rare but potentially fatal side- effect in children treated while suffering a viral infection PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN Discovered in the 19th century High toxicity of many forms discouraged use prior to 1949 Lacks the strong antiinflammatory effects of most NSAIDS Doesn't cause ulcers IS hepatotoxic, fatally so at high doses! PROPRIONIC ACID DERIVATIVES: Ibuprofen et al. very aspirin-like, except less ulcer activity Heavily advertised, but no better than aspirin unless severe gastric side-effects are involved OPIOID ANALGESICS EXTRACTS OF OPIUM POPPY (OR SYNTHETIC DERIVATIVES) ARE THE MOST POTENT ANALGESICS KNOWN All work at endogenous opioid receptors, especially the æ receptor And all have side-effects at other opioid sites in brain and body biological effects of the opioids: Analgesia via the æ opioid system Miosis - constriction of the pupils Respiratory depression Depression of the cough reflex Nausea Constipation, control of diarrhea Euphoria, hence abuse "Nodding off"; sedation not sleep Dependence, in that withdrawal is unpleasant + Most withdrawal effects are rebounds, due to up-regulation of opioid receptors + Withdrawal is not unlike a bad case of flu Tolerance and cross-tolerance: Tolerance increases by as much as ten-fold in a period of months, and cross-tolerance is shown to almost all opioids MAJOR CLASSES OF OPIOID ANALGESICS IN CLINICAL PRACTICE: Morphine: includes the codeines, heroin, and æ antagonists such as naltrexone Morphine itself is still made from opium Major first-pass effect means that oral administration is possible, but requires substantial dosages Codeine is better taken orally, has a strong ability to inhibit coughing, but less analgesia The Phenylpiperidines: synthetic compounds Meperidine (Demerol): very similar to morphine, but more efficacious given orally for control of pain Loperimide (Imodium) - common antidiarrhetic, Doesn't cross the blood-brain barrier, hence is not abused Fentanyl (Sublimaze) + Used with nitrous oxide or droperidol ( a neuroleptic) as in i.v. anesthetic + 50 times as potent as morphine! + Also used in transdermal patches for control of chronic pain Methadone: Good oral efficacy Much longer half-life than morphine Otherwise much like morphine Used for treatment of heroin addiction AND for control of chronic pain LAAM is a methadone congener which can be taken once every 72 hrs! Propoxyphene (Darvon) Has the lowest analgesic potency Almost always given with aspirin, for control of mild to moderate pain Very popular clinically due to misplaced concerns about the abuse potential of codeine