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218 Cards in this Set
- Front
- Back
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Morphine
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Strong Opioid Agonist
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Methadone
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Strong Opioid Agonist
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Meperidine
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Strong Opioid Agonist
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Meperidine trade name?
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Demerol
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Oxycodone
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Strong Opioid Agonist
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Oxycodone trade name?
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Oxycontin, Roxicodone
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Hydromorphone
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Strong Opioid Agonist
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Hydromorphone trade name?
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Dilaudid
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Fentanyl
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Strong Opioid Agonist
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Fentanyl trade name?
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Sublimaze
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Sufentanil
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Strong Opioid Agonist
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Sufentanil trade name?
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Sufenta
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Alfentanil
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Strong Opioid Agonist
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Alfentanil trade name?
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Alfenta
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Remifentanil
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Strong Opioid Agonist
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Remifentanil trade name?
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Ultiva
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Codeine
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Moderate Opioid Agonist
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Hydrocodone
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Moderate Opioid Agonist
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Hydrocodone trade name?
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Vicodin, Lortab
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Propoxyphene
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Moderate Opioid Agonist
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Propoxyphene trade name?
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Darvon
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Tramadol
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Opioid Agonist
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Tramadol trade name?
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Ultram
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Dextromethorphan
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Opioid Agonist
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Diphenoxylate trade name?
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Lomotil
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Loperamide
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Opioid Agonist
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Loperamide trade name?
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Imodium
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Buprenorphine
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Mixed Opioid Agonist-Antagonist
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Buprenorphine trade name?
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Buprenex
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Butorphanol
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Mixed Opioid Agonist-Antagonist
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Butorphanol trade name?
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Stadol
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Nalbuphine
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Mixed Opioid Agonist-Antagonist
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Nalbuphine trade name?
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Nubain
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Pentazocine
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Mixed Opioid Agonist-Antagonist
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Pentazocine trade name?
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Talwin
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Naloxone
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Opioid Antagonist
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Naloxone trade name?
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Narcan
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Naltrexone
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Opioid Antagonist
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Naltrexone trade name?
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Trexan, Revia
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Pain impulses are transmitted by
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primary afferent neurons to the spinal cord, where ascending connections from the spinothalamic tract neurons project to limbic structures and the cortex.
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Descending inhibitory fibers from the periaqueductal gray matter activate
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midbrain and spinal cord neurons that release enkephalins, serotonin, and norepinephrine. Opioids activate these pathways and thereby inhibit ascending pain impulses.
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Opioid drugs include
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strong and moderate agonists, mixed agonist-antagonists, and pure antagonists.
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In addition to analgesia, opioid agonists can cause
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sedation, euphoria, miosis, respiratory depression, peripheral vasodilation, constipation, and drug dependence.
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Opioid receptors can be divided into three types:
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mu, delta, or kappa opioid receptors. All types mediate analgesia
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Mu opioid receptors are primarily responsible for analgesic effects, as well as
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respiratory depression and opioid dependence of most clinical agents.
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The strong opioid agonists include
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morphine, fentanyl, meperidine, and methadone, which act primarily at mu opioid receptors. The first three of these agents are used to alleviate severe or moderate pain.
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Methadone is usually used in the treatment of
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opioid addiction (methadone maintenance programs).
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The moderate agonists produce maximal analgesia at doses that
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cannot be tolerated, so they are usually combined with a nonopioid analgesic.
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The moderate agonists, codeine, hydrocodone, and propoxyphene, are used to treat moderate or mild
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pain
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Other agonists include tramadol, a dual-action analgesic that
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activates opioid receptors and blocks neuronal reuptake of serotonin and norepinephrine.
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Buprenorphine, butorphanol, nalbuphine, and pentazocine are
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mixed opioid agonist-antagonists. These drugs exhibit partial agonist or antagonist activity at mu opioid receptors and exhibit agonist or antagonist activity at kappa opioid receptors. They produce less respiratory depression and are associated with a lower risk of drug dependence than are full opioid agonists.
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Naloxone and naltrexone are
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opioid antagonists
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Opioid antagonists are used to
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counteract the adverse effects of opioids in overdose or to prevent and treat alcohol and opioid dependence.
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Pain is
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an unpleasant sensory and emotional experience that serves to alert an individual to actual or potential tissue damage.
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Opioid analgesics act primarily in the
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spinal cord and brain to inhibit the neurotransmission of pain.
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Nonopioid analgesics act primarily in
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peripheral tissues to inhibit the formation of algogenic or pain-producing substances such as prostaglandins.
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Because most of the nonopioid analgesics also exhibit significant anti-inflammatory activity, they are called
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nonsteroidal anti-inflammatory drugs (NSAIDs).
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To facilitate the selection of an appropriate analgesic or anesthetic medication, patients are usually asked to describe their pain in terms of its
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intensity, duration, and location.
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Intense, sharp, stinging pain
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Aδ (fast) Primary Afferent Neuron
Neospinothalamic Ascending Pathway Reticular formation, thalamus, and sensory cortex Projections Pain localization and withdrawal reflexes |
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Dull, burning, aching pain
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C (slow) Primary Afferent Neuron
Paleospinothalamic Ascending Pathway Thalamus, periaqueductal gray matter, and limbic structures Projections Autonomic reflexes, pain memory, and pain discomfort |
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Opioid analgesics activate the
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descending pathways and directly activate opioid receptors on afferent nerve terminals and on STT neurons in the spinal cord.
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Nonopioid analgesics reduce the activation of
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primary afferent neurons via inhibition of prostaglandin synthesis.
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Pain can be further distinguished on the basis of whether it is
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somatic, visceral, or neuropathic in origin.
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Somatic pain is often well localized to
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specific dermal, subcutaneous, or musculoskeletal tissue.
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Visceral pain originating in thoracic or abdominal structures is often poorly
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localized and may be referred to somatic structures
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Cardiac pain is often referred to the
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chin, neck, shoulder, or arm.
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Neuropathic pain is usually caused by
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nerve damage, such as that resulting from nerve compression or inflammation, or from diabetes
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Neuropathic pain is characteristic of
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trigeminal neuralgia (tic douloureux), postherpetic neuralgia, and certain types of back and limb injuries.
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Exposure to a noxious stimulus activates nociceptors on the peripheral free nerve endings of
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primary afferent neurons
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The cell bodies of primary afferent neurons sit
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alongside the spinal cord in the dorsal root ganglia and send one axon to the periphery and one to the dorsal horn of the spinal cord.
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With noxious stimulation, substance P, glutamate, and other excitatory neurotransmitters are released from the
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central terminations of the primary afferent fibers onto neurons of the spinal cord.
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Many of these terminals synapse directly on spinothalamic tract neurons in the dorsal horn, which send long fibers up the contralateral side of the spinal cord to transmit pain impulses via
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ascending pain pathways to the medulla, midbrain, thalamus, limbic structures, and cortex.
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The primary afferent fibers transmitting nociceptive information are
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Aδ fibers and C fibers, which are responsible for sharp pain and dull pain, respectively.
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Ascending pain pathways consist of two main anatomical-functional projections:
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the sensory-discriminative component, to the cerebral cortex, and the motivational-affective component, to the limbic cortex.
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Projections to the sensory cortex alert an individual to the
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presence and anatomic location of pain
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projections to limbic structures (e.g., the amygdala) enable the individual to experience
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discomfort, suffering, and other emotional reactions to pain.
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The activation of spinothalamic neurons in the spinal cord are modulated by
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descending inhibitory pathways from the midbrain and by sensory Aβ fibers arising in peripheral tissues.
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According to the gate-control hypothesis pain transmission by spinothalamic neurons can be modulated, or gated, by
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the inhibitory activity of other types of large fibers impinging on them.
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The activation of spinothalamic neurons is also inhibited by
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peripheral Aβ sensory fibers that stimulate the release of met-enkephalin from spinal cord interneurons.
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The Aβ fibers are thought to also mediate the analgesic effect produced by several types of tissue stimulation, including
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acupuncture and transcutaneous electrical nerve stimulation (TENS). These mechanisms explain the pain relief that may be produced by simply rubbing or massaging a mildly injured tissue.
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The descending inhibitory pathways arise from
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periaqueductal gray (PAG) in the midbrain and they project to medullary nuclei that transmit impulses to the spinal cord
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The medullary neurons include serotonergic nerves arising in the
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nucleus magnus raphae (NMR) and noradrenergic nerves arising in the locus ceruleus (LC).
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When nerves release serotonin and norepinephrine in the spinal cord, they inhibit
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dorsal spinal neurons that transmit pain impulses to supraspinal sites.
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Nerve fibers from the PAG activate spinal interneurons that release an endogenous opioid peptide named
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met-enkephalin
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The enkephalins act presynaptically to
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decrease the release of pain transmitters from the central terminations of primary afferent neurons. They also act on postsynaptic receptors on spinothalamic tract neurons in the spinal cord to decrease the rostral transmission of the pain signal.
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Opioid analgesics activate the descending
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PAG, NMR, and LC neuronal pathways, and they also directly activate opioid receptors in the spinal cord.
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Since ancient times, opium, the raw extract of the poppy plant, Papaver somniferum, has been used for the treatment of
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pain and diarrhea
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During the 19th century, morphine was isolated from
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opium
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Later, specific sites in CNS tissue were discovered that bound morphine and other opioid agonists. The presence of stereoselective receptors for morphine in brain tissue indicated the likelihood of an
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endogenous ligand for these receptors, and this eventually led to the discovery of the three major families of endogenous opioid peptides: enkephalins, β-endorphins, and dynorphins.
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The opioid peptides are derived from larger precursor proteins that are
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widely distributed in the brain
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Endorphins and dynorphins are
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large peptides
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Met-enkephalin and leu-enkephalin are
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types of enkephalins small pentapeptides containing Tyr-Gly-Gly-Phe-Met/Leu.
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The enkephalins are released from neurons throughout the pain axis, including those in the
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PAG, medulla, and spinal cord. Enkephalins activate opioid receptors in these areas and thereby block the transmission of pain impulses. The enkephalins appear to act as neuromodulators in that they exert a long-acting inhibitory effect on the release of excitatory neurotransmitters by several neurons.
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Opioid agonists mediate their effects at three types of opioid receptors:
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mu (μ) opioid receptors, delta (δ) opioid receptors, or kappa (κ) opioid receptors. Most of the clinically useful opioid analgesics, however, have preferential or strong selectivity for mu opioid receptors. Some of the mixed opioid agonist-antagonist agents have kappa opioid receptor selectivity, but attempts to develop useful opioid analgesics selective for delta receptors have not been successful.
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Opioid drugs can be classified as
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full agonists, mixed agonist-antagonists, or pure antagonists
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Based on their maximal clinical effectiveness, the full agonists can be characterized as
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strong or moderate agonists
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Full agonists exert a maximal
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analgesic effect
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In humans, the strong opioid agonists are well tolerated when they are given in a dosage sufficient to relieve severe pain. The moderate opioid agonists, however, will
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cause intolerable adverse effects if they are given in a dosage sufficient to alleviate severe pain. For this reason, the moderate opioid agonists are administered in submaximal doses to treat moderate to mild pain, and they are usually formulated in combination with NSAIDs to enhance their clinical effectiveness.
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The mixed opioid agonist-antagonists are analgesic drugs that have varying combinations of
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agonist, partial agonist, and antagonist activity and varying degrees of affinity for the different opioid receptor types.
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The opioid antagonists have no
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analgesic effects. They are used to counteract the adverse effects of opioids taken in overdose and for the treatment of drug dependence.
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The opioid receptors are prominent members of the
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G protein-coupled receptor superfamily. Activation of opioid receptors leads to inhibition of adenylyl cyclase and a decrease in the concentration of cyclic adenosine monophosphate, an increase in K+ conductance, and a decrease in Ca2+ conductance. The activated Gαi subunit of the G protein directly inhibits the adenylyl cyclase enzyme, and the Gβγ subunits are thought to mediate the changes at the Ca2+ and K+ channels. These actions cause both presynaptic inhibition of neurotransmitter release from the central terminations of small-diameter primary afferent fibers and postsynaptic inhibition of membrane depolarization of dorsal horn nociceptive neurons.
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Morphine acts in the CNS to produce
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analgesia, sedation, euphoria or dysphoria, miosis, nausea, vomiting, respiratory depression, and inhibition of the cough reflex
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Analgesia is produced by activation of opioid receptors in the
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spinal cord and at several supraspinal levels
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Sedation and euphoria can be caused by effects on
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midbrain dopaminergic, serotonergic, and noradrenergic nuclei
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Surprisingly, many patients experience dysphoria after administration of
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opioids
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Miosis or constricted pupils is produced by the
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direct stimulation of the Edinger-Westphal nucleus of the oculomotor nerve (cranial nerve III), which activates parasympathetic stimulation of the iris sphincter muscle. Because little or no tolerance develops to miosis, this sign can be diagnostic of an opioid overdose.
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Codeine and other opioids inhibit the
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cough reflex at sites in the medulla where this reflex is integrated.
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The most prominent cardiovascular effect of morphine and many other opioids is
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vasodilation, which is partly caused by histamine release from mast cells in peripheral tissues.
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Morphine can cause
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orthostatic hypotension from decreased peripheral resistance and a reduction in baroreceptor reflex activity. In patients with coronary artery disease, the decreased peripheral resistance leads to a reduction of cardiac work and myocardial oxygen demand.
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Morphine and most other opioids act to increase smooth muscle tone in the
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gastrointestinal, biliary, and genitourinary systems. In the gastrointestinal tract, increased muscle tone leads to inhibition of peristalsis and causes constipation. For this reason, the opioids are the oldest and most widely used medication for the treatment of diarrhea. Unfortunately, chronic pain patients do not appear to become tolerant to the constipating effects of opioids, necessitating a continual need for laxatives and other agents.
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CNS Effects of Opioid Agonists
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Analgesia
Dysphoria or euphoria Inhibition of cough reflex Miosis Physical dependence Respiratory depression Sedation |
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Cardiovascular Effects of Opioid Agonists
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Decreased myocardial oxygen demand
Vasodilation and hypotension |
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Gastrointestinal and Biliary Effects of Opioid Agonists
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Constipation (increased intestinal smooth muscle tone)
Increased biliary sphincter tone and pressure Nausea and vomiting (via CNS action) |
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Genitourinary Effects of Opioid Agonists
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Increased bladder sphincter tone
Prolongation of labor Urinary retention |
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Neuroendocrine System Effects of Opioid Agonists
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Inhibition of release of luteinizing hormone
Stimulation of release of antidiuretic hormone and prolactin |
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Immune System Effects of Opioid Agonists
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Suppression of function of natural killer cells
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Dermal Effects of Opioid Agonists
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Flushing
Pruritus Urticaria (hives) or other rash |
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Morphine and other opioids also increase the tone of the
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biliary sphincter (sphincter of Oddi), and can cause an exacerbation of pain in patients with biliary dysfunction or a gall bladder attack.
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Opioids also increase the tone of the
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bladder sphincter and can cause urinary retention in some patients.
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The opioid agonist, meperidine, has less pronounced action on smooth muscle, it is the drug of choice for
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the pain associated with labor
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Opioids have an effect on
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neuroendocrine and immunologic function. In the hypothalamus, they stimulate the release of antidiuretic hormone and prolactin and inhibit the release of luteinizing hormone.
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Opioids also suppress the activity of certain types of
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lymphocytes, including natural killer cells, and this action may contribute to the high rate of infectious diseases in heroin addicts.
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The major adverse effect of morphine and other opioids is
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respiratory depression, which is usually the cause of death in severe overdoses. Opioids reduce the hypercapnic drive (the stimulation of respiratory centers by increased carbon dioxide levels) while producing relatively little effect on the hypoxic drive. Opioids reduce the respiratory tidal volume and rate, causing the rate to fall to three or four breaths per minute after an opioid overdose.
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As the cerebral circulation is exquisitely sensitive to CO2 levels and responds with an increase in cerebral blood flow, leading to increased intracranial pressure, opioids should not be used in the case of a
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closed-head injury
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The respiratory depressant effects of opioids are rapidly reversed by the intravenous administration of an opioid antagonist such as
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naloxone
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By stimulating the chemoreceptor trigger zone in the medulla, the opioids also cause
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nausea and vomiting. This is seen most often in ambulatory patients as opioids increase the sensitivity of the vestibular organ of the inner ear.
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Opioids cause mast cells throughout the body to release
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histamine, which can cause itching, or pruritus. A flushing reaction, noted by redness and a feeling of warmth over the upper torso, may also occur from histamine release.
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Allergic reactions to opioid analgesics are not
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uncommon. In most cases, however, a patient who is allergic to a particular opioid can use an opioid from a different chemical class. For example, someone who is allergic to codeine will probably not be allergic to propoxyphene or fentanyl.
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Tolerance is defined as
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a decrease in initial pharmacologic effect observed following chronic or long-term administration. Repeated administration of an opioid agonist will lead to pharmacodynamic tolerance for both the administered opioid and other opioid analgesics. Tolerance primarily results from down-regulation of opioid receptors.
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Tolerance develops to most of the effects of opioids but not to
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miosis and constipation
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Although considerable tolerance to respiratory depression occurs, a sufficiently high dose of an opioid can still
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be fatal to highly opioid tolerant individuals.
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Opioid tolerance is usually accompanied by a similar degree of
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physical dependence
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Physical dependence is defined as
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a physiologic state in which a person's continued use of a drug is required for his or her well-being. Tolerance and physical dependence appear with many drug classes and represent the establishment of a new equilibrium between the neuron and its environment (neuroadaptation), wherein the neuron becomes less responsive to the drug while requiring continued drug effect to maintain cellular homeostasis. If the chronic drug is abruptly withdrawn, the equilibrium is disturbed and a rebound hyperexcitability occurs owing to the loss of the inhibitory influence of the drug. This produces a withdrawal syndrome, the manifestations of which depend on the particular type of drug
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Because opioids demonstrate cross-tolerance, one opioid drug can substitute for another opioid drug and prevent symptoms of
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withdrawal in a physically dependent person. This is the basis for outpatient treatment of opioid dependence by the use of methadone or buprenorphine.
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The strong opioid agonists include naturally occurring drugs, such as
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morphine, and a number of synthetic drugs, including fentanyl, meperidine, and methadone.
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Morphine is the principal alkaloid of the opium poppy, Papaver somniferum, and constitutes about 10% of dried opium. Opium also contains papaverine, a drug sometimes used to
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relax smooth muscle and treat vasospastic disorders; noscapine, used as a cough suppressant, and minor amounts of codeine. The diacetic acid ester of morphine is heroin, a drug that is frequently abused.
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Morphine is well absorbed from the gut, but it undergoes considerable
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first-pass metabolism in the liver, where a significant fraction of the drug is converted to glucuronides. For this reason, larger doses are required when the drug is administered orally than when it is administered parenterally.
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The principal metabolite of morphine is
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the 3-glucuronide, which is pharmacologically inactive. A significant amount of the 6-glucuronide is also formed; it is more active than morphine and has a longer half-life. Hence, the 6-glucuronide contributes significantly to the analgesic effectiveness of morphine. Morphine is primarily excreted in the urine in the form of glucuronides. A small amount is excreted in the bile and undergoes enterohepatic cycling.
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Morphine is primarily used to treat
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severe pain associated with trauma, myocardial infarction, and cancer. In patients with myocardial infarction, it relieves pain and anxiety while also dilating coronary arteries and reducing the myocardial oxygen demand.
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Morphine is available in both parenteral and oral formulations, including
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long-acting oral formulations (Kadian, Avinza) that are useful in patients with chronic pain
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Fentanyl is a synthetic and highly potent
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opioid agonist. Fentanyl and its derivatives, including sufentanil, alfentanil, and remifentanil, are the most potent opioid agonists available. Indeed, tranquilizing darts used to sedate elephants and other large animals in zoos and in the wild are done using a fentanyl derivative called carfentanil (Wildnil).
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Because of its high potency and lipid solubility, fentanyl has been formulated in a long-acting
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transdermal skin patch (Duragesic) to provide continuous pain relief for patients with severe or chronic pain. It is also available for parenteral administration preoperatively and postoperatively and as an adjunct to general anesthesia.
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Fentanyl produces less nausea than does morphine, but is often associated with
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truncal rigidity when used as an adjunct parenteral anesthesia
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Fentanyl
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Route of Administration: Parenteral, transdermal, and transmucosal†
Duration of Action (Hours): 1 Elimination Half-Life (Hours): 4 Active Metabolite: No |
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Meperidine
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Route of Administration: Oral and parenteral
Duration of Action (Hours): 3 Elimination Half-Life (Hours): 3 Active Metabolite: Yes |
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Methadone
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Route of Administration: Oral and parenteral
Duration of Action (Hours): 8 Elimination Half-Life (Hours): 24 Active Metabolite: No |
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Morphine
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Route of Administration: Oral and parenteral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 3 Active Metabolite: Yes |
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Oxycodone
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Route of Administration: Oral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): Unkown Active Metabolite: No |
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Sufentanil
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Route of Administration: Parenteral
Duration of Action (Hours): 1 Elimination Half-Life (Hours): 2 Active Metabolite: No |
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Remifentanil
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Route of Administration: IV infusion only
Duration of Action (Hours): While infused Elimination Half-Life (Hours): 4 minutes Active Metabolite: No |
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Codeine
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Route of Administration: Oral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 3 Active Metabolite: Yes |
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Hydrocodone
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Route of Administration: Oral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 4 Active Metabolite: No |
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Propoxyphene
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Route of Administration: Oral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 9 Active Metabolite: Yes |
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Dextromethorphan
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Route of Administration: Oral
Duration of Action (Hours): 6 Elimination Half-Life (Hours): 11 Active Metabolite: No |
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Diphenoxylate
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Route of Administration: Oral
Duration of Action (Hours): 6 Elimination Half-Life (Hours): 12 Active Metabolite: Yes |
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Loperamide
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Route of Administration: Oral
Duration of Action (Hours): 6 Elimination Half-Life (Hours): 10 Active Metabolite: No |
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Tramadol
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Route of Administration: Oral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 6 Active Metabolite: Yes |
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Buprenorphine
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Route of Administration: Parenteral
Duration of Action (Hours): 5 Elimination Half-Life (Hours): 5 Active Metabolite: No |
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Butorphanol
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Route of Administration: Intranasal and parenteral
Duration of Action (Hours): 3 Elimination Half-Life (Hours): 3 Active Metabolite: No |
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Nalbuphine
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Route of Administration: parenteral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 5 Active Metabolite: No |
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Pentazocine
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Route of Administration: parenteral
Duration of Action (Hours): 4 Elimination Half-Life (Hours): 4 Active Metabolite: No |
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Naloxone
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Route of Administration: parenteral
Duration of Action (Hours): 2 Elimination Half-Life (Hours): 4 Active Metabolite: No |
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Naltrexone
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Route of Administration: oral
Duration of Action (Hours): 24 Elimination Half-Life (Hours): 12 Active Metabolite: Yes |
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Alfentanil and remifentanil are used as part of
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anesthesia procedures and are available for intravenous administration
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Remifentanil is especially useful for
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short-term procedures and out-patient surgery as it is considered to have an ultra-rapid onset of action, reaching blood-brain equilibrium and peak effect within 1 minute after the start of an intravenous infusion. It is also rapidly cleared by nonspecific esterases in tissue and blood, therefore recovery occurs within 5 to 10 minutes after the infusion stops.
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Meperidine is a synthetic opioid agonist with an unusual profile of pharmacologic properties. It has
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no antitussive activity and has variable effects on pupil size. Because its effect on gastrointestinal, biliary, and uterine smooth muscle is less pronounced than that of morphine, it is less likely than morphine to cause constipation or an increase in biliary pressure. Meperidine does not prolong labor as much as morphine does, so it can be used for analgesia in obstetrics.
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The parenteral formulation of meperidine is often used as an
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obstetric or postsurgical analgesic. The oral formulation is used to treat moderate to severe pain in the outpatient setting. The drug is converted to a toxic metabolite, normeperidine, which can cause CNS excitation, convulsions, and tremors when meperidine is administered in large doses or for a prolonged period. Hence, the drug is usually used for the short-term treatment of acute pain syndromes.
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Methadone is a
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long-acting synthetic opioid agonist. Although it is available in parenteral formulations, it is most often administered orally to ambulatory patients to treat opioid dependence or chronic pain. Use of the oral formulation by opioid-dependent patients can prevent their craving for heroin or other opioids, but it does not cause significant euphoria or other reinforcing effects. Because of its long duration of action, it can be administered once a day for this purpose. The treatment for opioid-dependent patients in this fashion is called a methadone maintenance program.
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Oxycodone is one of several
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semisynthetic morphine derivatives that are available as analgesics. Oxycodone is usually administered orally in combination with a nonopioid analgesic (e.g., acetaminophen) to treat moderate or severe pain. It is available as a single agent for acute treatment of pain (Roxicodone) and as sustained-release oral form of oxycodone (Oxycontin) for long-term treatment of chronic pain syndromes. The Oxycontin formulation is linked to several deaths of opioid abusers after they crushed the pills and dissolved the drug for intravenous administration.
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Because they do not produce maximal analgesia at doses that are well tolerated by patients, the moderate agonists are used at
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submaximal doses, almost always in combination with an NSAID analgesic. Fixed-dose combination products containing one of the moderate opioid agonists and acetaminophen, aspirin, or ibuprofen are available for the treatment of moderate pain.
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Codeine is a naturally occurring opioid obtained from
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the opium poppy. Structurally, it is the 3-O-methyl derivative of morphine. Because codeine contains a methyl group at the 3 position, the principal site of morphine metabolism, codeine undergoes a lesser degree of first-pass metabolism. Thus, codeine has greater oral bioavailability than morphine.
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Codeine is converted to morphine by cytochrome P450 isozyme CYP2D6, and persons with deficient variations of this isozyme obtain little pain relief from the drug. Conversely, pregnant and nursing mothers who are ultra-rapid metabolizers of codeine may pose a risk of
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lethal morphine exposure to the fetus or nursing infant. An FDA warning in 2007 noted that a published case report of an infant death raises concern that breast-fed babies may be at increased risk of morphine overdose if their mothers are taking codeine and are ultra-rapid metabolizers of the drug.
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Codeine is a less potent analgesic than morphine, and the doses required to obtain maximal analgesia produce intolerable side effects, such as
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constipation. For this reason, codeine is only available in combination with other agents (e.g., NSAIDs) to treat mild to moderate pain. Codeine also produces a significant antitussive effect and is included in many cough syrups to alleviate or prevent coughing.
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The uses of hydrocodone are similar to those of codeine. Like codeine, it is only available in
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combination medicines, primarily with an NSAID such as aspirin or acetaminophen, in more than 15 different formulations.
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Propoxyphene, a chemical analogue of methadone, has much weaker opioid agonist properties. Propoxyphene has about half the analgesic activity of codeine when administered in usual therapeutic doses. It is most frequently used in
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combination with acetaminophen to treat mild to moderate somatic and visceral pain. Propoxyphene is usually well tolerated, but prolonged administration can lead to the accumulation of a toxic metabolite.
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Tramadol is a unique dual-action analgesic. It is an agonist at
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mu opioid receptors and inhibits the neuronal reuptake of serotonin and norepinephrine.
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Tramadol is administered orally to treat
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moderate pain. It has a definite but limited drug dependence liability. Nevertheless, it has been used successfully in the treatment of chronic pain syndromes and produces minimal cardiovascular and respiratory depression. The drug lowers the seizure threshold, and the risk of seizures is increased if tramadol is used concurrently with antidepressants.
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Dextromethorphan, which has significant antitussive activity and is used in the treatment of
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cough
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Diphenoxylate and loperamide, which activate opioid receptors in gastrointestinal smooth muscle and are used in the treatment of
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diarrhea
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Mixed opioid agonist-antagonists are drugs that exhibit
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partial agonist or antagonist activity at mu receptors and show agonist or antagonist activity at kappa receptors. Examples are buprenorphine, butorphanol, nalbuphine, and pentazocine.
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Mixed opioid agonist-antagonists have a large chemical group on the nitrogen atom of the morphine molecule, which is responsible for their
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partial agonist or antagonist activity at opioid receptors.
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All of the agonist-antagonists can be given
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parenterally
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Pentazocine is available for
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oral use
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Butorphanol is available as a
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nasal spray. Butorphanol is rapidly absorbed from the nasal mucosa, which thereby enables the use of the drug on an as-needed basis.
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The most important pharmacologic property of mixed opioid agonist-antagonists with respect to their clinical activity is the lack of
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full agonist effects at mu opioid receptors. Because of this, the mixed opioid agonist-antagonists produce less respiratory depression as the doses are increased than do strong opioid agonists such as morphine. Hence, the mixed opioid agonist-antagonists are safer to use with regard to respiratory depression and overdose. They also appear to have a lower liability for drug dependence and abuse than do full opioid agonists. The mixed opioids produce less constipation than do most of the full agonists.
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The mixed opioid agonist-antagonists can cause
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anxiety, nightmares, and psychotomimetic effects, including hallucinations, as a result of the activation of kappa opioid receptors. They can also precipitate withdrawal in a person physically dependent on a full opioid agonist.
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Parenterally administered agonist-antagonist drugs are primarily used for
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preoperative and postoperative analgesia and for obstetric analgesia during labor and delivery. The orally and nasally administered drugs are used to alleviate moderate to severe pain.
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Buprenorphine, which is a partial agonist at mu receptors, is noted for a
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slow dissociation from the mu opioid receptor after binding. It is somewhat longer acting than most parenterally administered opioid analgesics and can be administered intramuscularly or intravenously. It was recently approved for outpatient treatment of opioid dependence. It is available in an oral and sublingual formulation combined with naloxone to prevent intravenous abuse.
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Butorphanol and nalbuphine, are
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kappa opioid receptor agonists, and have partial agonist or antagonist activity at mu opioid receptors. Both drugs are administered parenterally, and butorphanol is also available as a nasal spray.
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Pentazocine is a
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kappa opioid receptor agonist with additional activity at sigma (σ) receptors. Sigma receptors were once considered a type of opioid receptor; it is now known that they are a distinct class of receptors mediating the psychotomimetic effects of phencyclidine (PCP) and ketamine. Pentazocine is available for parenteral and oral use. The parenteral formulation is primarily used as a preanesthetic medication and as a supplement to surgical anesthesia.
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The oral formulations of Pentazocine are used to treat
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moderate to severe pain, and one of them contains naloxone, a pure opioid antagonist, to discourage parenteral abuse of the drug.
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Parenteral use of an oral pentazocine formulation can cause
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severe cardiovascular effects, especially in patients with existing cardiovascular disease. Pentazocine is also available in combination with aspirin or acetaminophen for oral administration.
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Naloxone and naltrexone are
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competitive opioid receptor antagonists that can rapidly reverse the effects of morphine and other opioid agonists. These pure opioid antagonists have two primary clinical uses: the treatment of opioid overdose and the treatment of alcohol and opioid dependence.
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Naloxone and naltrexone are
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chemical analogs of morphine, with bulky chemical groups attached to the morphine molecule. This modification allows the molecule to bind to the opioid receptor but prevents the conformation change in the receptor required for agonist activity.
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In cases of opioid overdose,
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naloxone is administered intravenously to rapidly terminate respiratory depression and other toxic effects of opioid agonists. Because naloxone has a relatively short half-life, repeated doses of the drug may be needed to counteract the effects of the longer-lasting opioid agonists.
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Naloxone is also formulated with opioid agonists in oral medications to prevent
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crushing of the pill and intravenous abuse. Because naloxone has low bioavailability and is not effective when given orally, it does not block the effects of the oral opioid but would block opioid effects or even precipitate withdrawal if used by the intravenous route.
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Naltrexone, in oral (Revia, Depade) and extended-release injectable suspension (once-a-month, Vivitrol) formulations, is also used to treat
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alcohol and opioid dependence. In contrast to naloxone, naltrexone has high oral bioavailability and can be used on a long-term basis by opioid addicts who have undergone detoxification and are no longer using opioids.
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As a general rule, patients with acute or chronic pain should be treated with
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the least potent analgesic that will control their pain. Mild pain usually responds to a nonopioid analgesic, usually an NSAID. Moderate to severe pain is often treated with codeine, hydrocodone, or oxycodone in combination with a nonopioid analgesic.
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Severe pain usually requires the use of a strong opioid agonist such as
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fentanyl, meperidine, methadone, or morphine
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Although meperidine can be used for acute postsurgical pain and in other situations in which the duration of treatment is limited to a few days, it should not be used for
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longer durations, because of the possible accumulation of a toxic metabolite (normeperidine).
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Acute pain caused by trauma, surgery, or short-term medical conditions can be effectively managed with an analgesic and appropriate treatment of the underlying condition. In patients with acute pain, the risk of producing drug dependence is
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extremely low. Hence, physicians and other health care professionals should not hesitate to administer adequate doses of a sufficiently strong analgesic to control pain
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Pain associated with arthritis, neuropathy, and other chronic but nonterminal conditions is more difficult to treat and is often managed with a combination of
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analgesics, co-analgesics, psychotherapy, physical therapy, and other treatment modalities. Use of opioid analgesics in the treatment of chronic pain is associated with a risk of opioid tolerance and physical dependence, so care must be exercised to prevent dosage escalation, drug dependence, and prescription drug abuse.
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Patients with terminal illnesses, such as metastatic cancer, should receive sufficient doses of opioid analgesics to control their pain, irrespective of any concerns about
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the development of tolerance and physical dependence.
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Giving analgesics on an as-needed basis sometimes produces
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wide swings in pain and sedation during the early phase of treatment. Therefore, in the initial stages of acute pain, analgesics should be given around the clock at regular intervals. The dosage should be titrated to control pain while minimizing sedation and other side effects. As the pain subsides over time and the need for analgesia decreases, the patient can be transferred to an as-needed schedule of medication.
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Patient-controlled analgesia is
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a method of intravenous administration that permits the patient to self-administer preset amounts of an analgesic (e.g., fentanyl) via a syringe pump that is interfaced with a timing device. The method enables the patient to balance pain control with sedation. Its use depends on the patient's ability to activate the device, so it may not be suitable for elderly patients or for patients immediately after surgery or trauma.
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If pain is associated with inflammation,
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nonopioid drugs with anti-inflammatory activity can be especially useful.
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If pain is associated with peripheral nerve or nerve root sensitization, treatment with
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transcutaneous nerve stimulation or a local anesthetic may help
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Capsaicin activates
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peripheral nociceptors on primary sensory neurons, thereby leading to increased release of substance P and eventually to the depletion of substance P in the CNS. Capsaicin produces a burning sensation for the first few days of application, but this is gradually replaced by an analgesic effect.
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Chronic pain is frequently seen in association with
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systemic disorders (e.g., diabetes).
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When pain has been present for a period of time, the responsiveness of dynamic wide-range nociceptive neurons in the spinal cord increases in a way that
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increases pain perception and memory. As these neurons become "wound up," their receptive fields increase so that pain is felt over a larger area. These changes appear to contribute to the maintenance of chronic neuropathic pain. Patients with this type of pain may benefit from a combination of nonpharmacologic therapies (e.g., TENS, acupuncture, and physical therapy), analgesic medications, and co-analgesic drugs.
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The most widely used co-analgesics are the
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antiepileptic drugs and the antidepressant drugs. These drugs provide pain relief in chronic pain syndromes and may potentiate the effects of opioid and nonopioid analgesics
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Carbamazepine, gabapentin, phenytoin, and valproate are
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Antiepileptic drugs
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Antiepileptic drugs are
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particularly effective in treating pain syndromes with an intermittent lancinating quality, such as trigeminal neuralgia and postherpetic neuralgia. They are also useful in syndromes characterized by continuous, burning neuropathic pain. They probably act by inhibiting the conduction of pain impulses in the CNS, but their exact mechanism is unknown.
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The tricyclic antidepressants are the
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most widely used type of antidepressants for the treatment of chronic pain, as they may be more effective than the selective serotonin reuptake inhibitors in this respect.
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Amitriptyline, desipramine, and other tricyclic antidepressants are particularly effective in the
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management of postherpetic neuralgia, diabetic neuropathy, migraine headache, and neuropathic pain syndromes. They can also be beneficial in the management of pain associated with chronic fatigue syndrome.
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Tramadol is a dual-action analgesic that combines
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opioid receptor activation with inhibition of neuronal reuptake of neurotransmitters in a manner similar to tricyclic antidepressants. Tramadol is effective in many chronic pain syndromes and causes little constipation, respiratory depression, or drug dependence.
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Most cancer patients can be managed with oral medications, including
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opioid and NSAID analgesics, antidepressant drugs, and antiepileptic drugs. Acupuncture, TENS, and other modalities are also useful.
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Severe cancer pain usually requires the administration of a
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strong opioid agonist (e.g., fentanyl, methadone, or morphine). To maintain stable serum drug levels and prevent breakthrough pain, it may be helpful to use a long-acting preparation (e.g., sustained-release morphine tablets or transdermal fentanyl skin patches), either alone or in combination with a rapid-acting preparation, such as morphine oral solution.
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