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Principles of opioid pharmacotherapy: Practical implications of basic mechanisms
S#mial &tion
OS Opioids fw Nonmalignant
Pain, Pati 2’
Principles of Opioid Pharmacotherapy: Practical Implications of Basic Mechanisms
Our knowledge of opioid pharmacology has proprrsscd grcady in the last two dcradm. This enhanced understanding has. unfortunately. provided an opportunity for confusion tn nomenclature. The word @urn is derived from the Greek. meaning ‘$ncc*’ (l.c.. juice of the poppy plant). Opium is obtained from the unripe seed caps&s of the poppy plant and is a dried powdcrcd mixture containing approximately 20 alkaloids. An opta& is an alkaloid (i.e.. any agent dcrtvcd from opium). All cndogcnous and exogenous (natural cr syn thctic) compounds that -5 morphinelike analgAc propcrtics arc termed +a&. Thus.
Addms wfmnf rques” IO F Mlrharl Fcrnntr. MD. Gnccr Pam and Symprom .Wanagrmrnt Prognm. tlcnpnal of the Un~vrn~ry of Pcnn\ylvann. 4th Floor Ravdm Courtyard Bulldmg 3400 Spruce Strcc~. Phlladclphta. PA 19104. US4 ‘Pan 1 of the sprrid &c&a Q opioidr+ nmd Ihk appnn in Volume II, Number JountaJ o/Patm and Symptom Mowgrwwar 0 u s Gncrr Pam Rdwf C-urc. 1996 Pubtithed by E.&virr. Nirr York. Nrr York
&IUIII+ 4. of thr
the correct “PCIICVIC” agents is “optAd.“’
term
for
thus class of
The alkaloids of opium can bc chcntically subnividcd lntcl IWO group,: the phcnanthrcncs and the benzylisoquinoloncr. Morphine, cndcinc. and th&ainc arc the principal phcnanthrcnc alkaloids dcrivcd from opium (Table 1). Papavcrinc (a ~asodilator) and no+ capmc (both lacking morphine-like propcrtics) arc the principal bcnzyiisoquinoloncs. Morphine is the prototypic opiord. The molecular 5kcltton of morphine is composed of fivr intcrlorkcd rings (Rgurc I). Substitution of chemical constituents on the skeleton gcncntes the scmi-synthcuc opi&ds (Table I) Synthetic opioids (Table I) arc crcatrd by reduction of the number of fused rings (Fig urc 2). Despite chrngcs in the number of ring. a common “T-shaped” core is found in all opioids. A pipcridinc ring forms the cros.+ bar (and is believed to confer “opioid&kc” aW&92~/WSl500 s3.M 0885~4t%~aI!io14
Endopous
opioid Pr$tuGs
The cndogwous opio~&’ form p~rc of on cndogcnous analgesic system (con~nm~ng cnkcphalincrgic. rrotoncrgic. and nondrcnrqic pahw~n). All mdogcnous oplo~rb contin IJIC a,.,,,~ acid squrncc rrm,aw&on~ &rmr++.n, Idamtn~ Thry arc formed hv clcavagc 9‘ larger prccunor molctuln and can lx g -0.1pcd arcording~. Both mctaAcphalin and Icu+nkcphahn UC dcrirtl from procnkrphahn A Entcpha. lim mr ¶nmalolopiully laaliud IO arcu of the ccnurl nervous ryucm KISS) eurntial for antinociccpion. Thy UC l bo found in Lhc gaumintinal uacl. sympathetic ncrwxn 9% um. and adrenal medulla. &cndorphin is the most po~cn~ of rhc endogcnousopioiandisfoundmrhchvpcr thalrmus. periqueduc~l g-y maucr. and locus ccndcus. @aadorphm I) gcncnwd from clcangc of pro-op~omrlanotorcin and IS rclcased in a one-toanc molar ratio rrich xircnncortkotmpic honnonr (ACTH) from the pituitary. Dynorphin (IJIC prototypic ligand of the ai-cccptor) and a+wncodorphin am drnrrd from prodynorphin (procntcphalin-B). De@ having -totopk loalization simtiar to thaw of the mkcphahm. rhc dynorphinr pcum no ywrnt atu!g&c propmies.
opwld
Rfrrpfon
Opioib, produce their analgesic cllccl b mimlcking the actions of cndogcnous opioid pcpdc+ at spccdic rctcpton wilhm the CSS.’ The rcccp~or ran be viewed as a common molcculu site of action for a diwnc group of compounds. The receptor mediates IWO functions: chemical rccognilion and c~ologic action. Thaw functions arc locahrcd IO dilTercnt phnical areas of Ihc receptor complcr. Only Ic\orolrlon iwlncn posxss rnalg&c acwily and. chcrcforc. Ihc recognium ire b highly specific.” Binding finity r&n 10 the ww@ of auxhmcnt of chc opoid u) the rrcrpor iu. as opioids wall bind IO the recognition WC with varying strength.” It is posibk to dctcrmine lb rank order of binding affinitio using r-uiau hinmny spuna. R-u binding aBinL ties correlate quite clos.+y with the analgesic polcocio of the opioids.’
Thcrc
arc scvcral lvps of opioid rcccpton of nhirh mediate an arrav of pharmacologic cfiecu“” Mew opiolds hind to “morphineprcfcrring” or p-rcccp~orr hndorphin is rhc prototypic cndogcnous ligand. and morphine n the wototyic cxqcnous ligand. Using autoradiographv. prcccpton haw bcn found .n highconccnuatiom in an-u of the brain that mediate opioid-ioduccd analgesia Tbcsc areas include the pcriaqucducul pay. rhc m&us nphr magnus. and tJw medial chalamus.‘~” Other opioid rcccpcon Lhac pro&cc analgcsic cfkcu (b and r-rcccpton) are found mainly in Lhc spinal cord. While yrcccpron arc found a8 the Icvcl of the spinal cord, activation ol prrccpcoo ir ‘argcly rc5ponsiblr for wpraspinal analgea 730 subtypes of p-rctcpcon have hccn dcmtinsu-ated.““* Acthauon of )r,-rccepton
(Table
2). cwh
Vd
268
II No. 5 hfq
19%
AgonisLI Morphmc Me lidinr romorphonc d Oxymorphmc lnwphnnol Fenunyi Sufenunil Alfenonil Mclhadonc Agonirt-anogoniw Buprcnorphine Bwx-phanol
Nalbuphinc PrnuuKlnC fkmcLnc
Dynorphin is c)ar prototypic cndogcnous agw nist. Morphine also acts a a &agonist. However. the relative affinity of morphine for the r-receptor is 200 times less than its afFinity for the p-receptor. Analgesia attendant IO the opioid agonist-antagonists is mainly derived from r-rcccptor activation. In vitro binding studies in the rat vas deferens have described the c-receptor, though it is not well character&d. bndorphin is the prcl posed cndogcnous agonist. Ar Btndorphin is released in a one-tmnc molar ratio with ACTH from the pituitary gland, the c-receptor may mediate a hormonal effect of pndorphin. Another poorly characterized receptor that has been proposed as an opioid receptor in the past is the o-receptor. The agonistantagonist opioids at least partially activate the o-receptor, producing psychotomimetic effects including dysphoria and hallucinations. as well as tachycardia, tachypnca. and mydtiasis.
Inhittsic Ackdy: The &Uionsh$ Bduwn Rrwpx Binding and Responst The intensity of physiologic actions produced by exogenous administration of an opioid defines its intinsic activity. Agaictc pr* duce a maximal biologic response through receptor binding. Anfqnirlr (naloxcne) have low or no intrinsic activity and reverse or inhibit the effects of agonists by preventing receptor acccu.*s Padal agt3xisl.t produce a
submaximal response at the receptor even at high doses (e.g.. buprcnorphinc’s action at the p-receptor). Opioids can have divergent activities at different recepton, simuhaneously acting as an agonist at one and an antagonist at another. These opioids are termed ngonisl-cnfagoni& or m&d dgati*nlogonuf.~.“~~’ Pentazocine is a weak competitive antagonist at the yrcccptor, a strong rc-agonist. and a u-agonist. Nalbuphine rcvcrses opioid-mediated respiratory depression through p-receptor antagonism but analgesia through partial provides r-agonism. ” Table 3 lists the interactions of opioids at Mrious receptor subqpes. The agonist-antagonists also exhibit characteristic pharmacologic properties: (a) the slope of the dose-response curve is less steep than that of a full agonist (Figure 3); (b) the dosc-responsc curve exhibits a ceiling effect (i.e., a submaximal response as compared with a full agonist) (Figure S); and (c) concomitant administration of an agonlst-atttagonist and full agonist can reduce the effect of the full agonist.
The Gmqi#
of Equianalgaic
The “potency” or intensity cflcct of individual opioids upon: (a) access to the receptor.
Dosing of analgesic is dependent and (b) bind-
phenomenon suggests potency of some opioith repetitive dosing.”
The Oral lo Pamite&
Fig. 3. The cot8ccpt of intrinsic activity. Full agonists produce a maximal biologic responu (e.g.. analgc sia. respintory deprcsrion. etc.). while partial age nius produce ? submaximal response en at high doses. Antagonists
rcwry
the biologic
rqonsc
to
opioids. Tltcreforc. their effect is liied as zero in the figure. (From reference 62. witb Permission.) ing aflinity (“fir” at the receptor site). Access to the receptor for p-agonists is dependent upon physicochemical and pharmacokinetic properties: (1) partition coefhcicnr. (2) pKa, (3) the degree of ionization, (4) unbound fraction of a dose, (5) apparent volume of dis tribtttion, (6) clearance. and (7) the rotttc of administration. Therefore. apparent differences in potency among opioids are primarily the result of physicochemical and pharmacokinctic differences among individual opioids and not a function of pharmacodynamic dis tinctiotts. Thus. all opioids can be made quipotent or qttianalgesic by adjusting for phyicochcmictl and pharmzcokinctic differences by correcting for dosage and route of adminis uation. This concept is extremely important in the clinical use of opioidsnsn It is important to emphasii that quianalgesic convenion schemas can only he used as guidelines. Practitioners should not be dogmatic in their interpretation. as certain mcthodological problems are inherent in the genesis of such convenion tables.
hcomphc
Cross-Tokranu
Patients can become tolerant to the analgesic effects of a given opioid. In such cases, another opioid can be substituted to provide helter analgesia, as opioids exhibit incomplete crostolennce.“” Clinical exp-ricncc shows that onehalf of the qttianalgesic dose of the new optoid may be used for initial dosing. This
that may
Puncy
the relative increase with
mio
The bioavailabiity of otal morphine varies between 15% and 64%, with an average oml bioavaiiability of 3l3%.s’ Therefore, morphine has significant first pass metabolism. which must be taken into account when convening from oral i3 parcntetal adminisuatioc.” For acute pain and single doses, the oral to parentcnl potency ratio for morphine is 1:6.s’ For chronic pain and multiple doses, the oral to parcntetal potency ratio for morphine is I:2 or 1:3.s’-“-w These ratios have been empiticalty adopted for oral IO parcntctzt convcnion for otlwr opioids.
771~ ,#Cpivk oJ Potency Among Pamntmd Routes The intramuscular (IM). subcutaneous (SC). and intravenous (lV) routes of adminis ttation are assumed to be quipotenr in many conversion schemes, thereby assuming cquhalent bioavail&lity among the three routes of administration. Few data exist to validate this assumption. however. and several authon have questioned it. In a study by Urquhart and colIcagues.K patients receiving hydromorphone vka SC PCA had significantly higher dosage requirements in comparison to patients recciving lV PCA. thereby suggesting ttnqttal bto availability. According to Urquhart and colleagues,% the subcutaneous to intravenous potency ntio is l:1.5 or l:2.
RtspirafiAm All p-agonists and the partial agonist buprcnorphinc produce a dosedcpendent reduction in the responsiveness of brainstcm respiratory centers to increases in carbon dioxde tension (PC0,).“7-w This reduction in responrtveness t.s chatactcrized by an increase in resting PCOs and diplaccmcnt of the CO, response CUM 10 the tight.” Eqttianalgesic doses of p-agonists will produce a similar degree of respiratory depression and an quimlcnt shift of the CO, response curve to the righ~“~’ Opioid agonists also depress the
FtT?DWt
270
T&k opioid
E4phdgd
4 Dosing
gcsic dosages, opioids differ potential to produce slcep.ti
&pivaknoEqu;maFc*c
Opioid
ROUIC
Morphine
Paremetal or.4 PXenlCnl Old PUenlCnl oral RWltenl Oral Rrcntcral Oral Psrenteral Onl Parentcral 0-l Parcnterrl Onl
Cdeinc oxycodonc Lcvorphanol Hydromorphonc Meperidinc Methadone Fentanyl
IO 30 130 200 15 30
2
bid II No. 5 hia7 19%
mg mg mg mg mg mg
w
4 mg I .5mg 7.5mg 75 mg sm mg IO mg m w3 t.JdLLL
pontinc and medullary centers involved in regulating the rhythmicity of breathing. Depression of these centers results in pro longed apnea between breaths, delayed exhalation, and periodic breathing.s’.% Mixed agonist-antagonist opioids do not produce dose-related respiratory depression but exhibit a limited or “ceiling” effect.“’ Agonist*ntagonists displace the CO, response curve to the right, but the curve is chatacteristically “bclkhaped” when these opioids are given in increasing doses.” Changes in Cognition, Alerfneq and Mood Opioids cause alteration in mood. PaGents report feelings of warmth, drowsiness, and sometimes well-being or euphoria. Alterations in mood are believed IO be mediated through the limbic system.” At sttfhdendy high doses, opioids may cventually produce sleep. However, unconsciousness is not a certainty even it high or “anesthetic” doses. Arousal may still be produced by noxious stimulation’s Moreover, at quianal-
in their
intrinsic
Tolerance, Physical Ikpndence, and Addiclion Continued exposure of the receptor to high roncentrations of opioids can cause tolerance. Tolerance refcn to the progressive decline in potency of an opioid with continued use. so that increasingly higher concentrations are tcquired to achieve the same analgesic effect. The phenomenon is characteristic of opioids as a class of analgesics and is receptor mcdiated. When tolerance develops to a particular opioid. cross-tolerance to other opioids concomitantly develops, though such tolerance is incomplctc. Physical dependence does not in any way imply addiction. Physical dependence is a physiologic state characterized by withdrawal (abstinence syndrome) after discontinuation of the opioid. Yawning, diaphorais. lactimadon, coryza. and tachycardia arc the initial manifestations of the abstinence syndrome. Later, abdominal cramps, nausea, and vomiting occur and peak at approximately 72 hr. Tolerance to the opioid is quickly in*.t during withdrawal. Addiction is defined by the World Health Organization as: A sute. psychic and sometimes also phyical. resulting from the interactions between a living organism and a drug, characterized by behavioni and other responses that ahrap include a compulsion to take the drug on a continuous or periodic basis in order to expc ricncc its psychic cflccw. and sometimes to avoid the discomfort of its alxence. Tolcrancc
may or may not be present.‘” In the popular mind, addiction is a compulsion to obtain a drug in order to experience its psychic effects. The definition of the World Health Organization closely approximates such a conception. Once again, it is important to emphasize that addiction implies compulsive behavior and psychologic dependence. Tolerance (a pharmacologic property of a class of drugs) and physical dependence (a physiologic effect also characteristic of this class of drugs) are conceptually and phenomenologically distinct from addiction. Can administration of opioids iatrogenically cause addiction? A prospective study has examined the incidence of opioid addiction in 12.C00 hospitalized patients receiving at least
one dose of an opioid.* Only four reasonably welldocumented cases of subsequent addiction were demonstrated in patients without a prior history of drug abuse. Thus, opioid addiction may be a tare iatrogenic event, particularly when opioids are used to treat pain.”
Effects Ujmn the Gastroinhzstinal Tract The propulsive peristaltic contractions of both the small and large intestines are decreased by opioids. At the same time, the amplitude of nonpropulsive. rhythmic, segmental contractions is enhanced. In the upper gastrointestinal tract, opioids cause decreased gastric motility while increasing anttal tone. Wtth concomitant enhanced tone in the first part of the duodenum, delayed gastric emptying may result. Sphinctetic tone is increased by opioicb in th e pyloric and anal sphincten and ileocecal valve. Increased tmnsit time is produced by coupling decreased propulsive activity with enhanced sphinctetic tone. Constipation results from the delay in passage of intestinal contents. allowing for greater absorption of water, increased viscosity, and desiccation of bowel contents. The peripheral and central mechanisms underlying the effects of opioids upon bowel motility are unclear.” With respect to peripheral mechanisms, opioils affect choline@. serotonergic, and enkephalinergic receptors located in the myenteric plexus of the intes tine. With respect to central mechanisms, the effects of neutaxial administration of opioids are not inhibited by systemic ganglionic blocking agents or the removal of the extrinsic innervation of the bowel.‘” Moreover, injection of morphine into the cerebral ventricles inhibits bowel motility. huraventricular administration of naloxone or vagotomy can inhibit or revetse this effect” Thus, there is substantial evidence to suggest that both local and central mechanisms are involved in opioidinduced changes in bowel motility.
Biliary Tract p-agonists produce a marked increase in biliary tract pressure. Pressure within the common bile duct may increase tenfold after the subcutaneous injection of IO mg of morphine.” A much less marked increase in biliary pressure is seen after administration of agonist-antagonists.“’ Moreover, nalbuphine
has been reported to actively reverse sphincter of Oddi spasm. However, analgesia is still maintained (x-receptor analgesia).ss
Gudiova.uulur
Eflkcts
Opioids produce chronotropic. inotropic. and peripheral vascular changes. Opioids pro duce a dose-dependent btadycardia due to central stimulation of the vagal nucleus in the medulla.5’~5’ As the bradycardia is vagally mediated, it can be blocked with atropine.“s The exception to this phenomenon is the administration of meperidine, which may cause tachycardia. Meperidine is structutally similar to atropine. Negative inotropic effects may be produced by meperidine at doses as low as 2.0-2.5 mg/kg.5’55 Otherwise, opioids maintain normal myocardial contractility at clinically useful dosages. All opioids can reduce direct myo P but this effect cardial depression,“.“.s is often not seen even with anesthetic dosages. Morphine has both a direct effect on vascular smooth muscle and an indirect effect through the release of histamine. Arteriolar dilation and venodilation are thereby pro duced.Histamine release b belicved to be the primary mechanism underlying vasod&tion with morphine. Meperidine and codeine also release histaminz. Fentanjl and sufentand do not6’.ez
This brief review has described some of the salient characteristics of opioid drugs. The literature pertaining to opioid pharmacology is extensive and relevant to the clinical use of these drugs. Recent review are available and can provide rich detail about basic and applied considetations.‘““s’sc
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Vd 11 h’o. 5 My
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49. McCammon RL. Stoelting RR. Madura JA. ElTecw of butorphanol. nalbuphinc. and fentanyl on intrabiliary tract dynamic% Anesth Analg 1984; 65:13%142.
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59. Humphreyr HR. Fleming &“. Opioidinduced spasm of the sphincter of Oddi apparendy rwerscd by nalbuphine. Anest! Analg 1992;74:SO%310.
64. Smelting RR Opioid agonists and anqoni%Is In: Stoelting RK Pharmacology and phpiology in anesthetic practice. Philadelphia: lippincocr 19l37: *iOl.
51. Reitan JA, Srengert
RB. Wymore
MC. Mnnucci
OS Opioids fw Nonmalignant
Pain, Pati 2’
Principles of Opioid Pharmacotherapy: Practical Implications of Basic Mechanisms
Our knowledge of opioid pharmacology has proprrsscd grcady in the last two dcradm. This enhanced understanding has. unfortunately. provided an opportunity for confusion tn nomenclature. The word @urn is derived from the Greek. meaning ‘$ncc*’ (l.c.. juice of the poppy plant). Opium is obtained from the unripe seed caps&s of the poppy plant and is a dried powdcrcd mixture containing approximately 20 alkaloids. An opta& is an alkaloid (i.e.. any agent dcrtvcd from opium). All cndogcnous and exogenous (natural cr syn thctic) compounds that -5 morphinelike analgAc propcrtics arc termed +a&. Thus.
Addms wfmnf rques” IO F Mlrharl Fcrnntr. MD. Gnccr Pam and Symprom .Wanagrmrnt Prognm. tlcnpnal of the Un~vrn~ry of Pcnn\ylvann. 4th Floor Ravdm Courtyard Bulldmg 3400 Spruce Strcc~. Phlladclphta. PA 19104. US4 ‘Pan 1 of the sprrid &c&a Q opioidr+ nmd Ihk appnn in Volume II, Number JountaJ o/Patm and Symptom Mowgrwwar 0 u s Gncrr Pam Rdwf C-urc. 1996 Pubtithed by E.&virr. Nirr York. Nrr York
&IUIII+ 4. of thr
the correct “PCIICVIC” agents is “optAd.“’
term
for
thus class of
The alkaloids of opium can bc chcntically subnividcd lntcl IWO group,: the phcnanthrcncs and the benzylisoquinoloncr. Morphine, cndcinc. and th&ainc arc the principal phcnanthrcnc alkaloids dcrivcd from opium (Table 1). Papavcrinc (a ~asodilator) and no+ capmc (both lacking morphine-like propcrtics) arc the principal bcnzyiisoquinoloncs. Morphine is the prototypic opiord. The molecular 5kcltton of morphine is composed of fivr intcrlorkcd rings (Rgurc I). Substitution of chemical constituents on the skeleton gcncntes the scmi-synthcuc opi&ds (Table I) Synthetic opioids (Table I) arc crcatrd by reduction of the number of fused rings (Fig urc 2). Despite chrngcs in the number of ring. a common “T-shaped” core is found in all opioids. A pipcridinc ring forms the cros.+ bar (and is believed to confer “opioid&kc” aW&92~/WSl500 s3.M 0885~4t%~aI!io14
Endopous
opioid Pr$tuGs
The cndogwous opio~&’ form p~rc of on cndogcnous analgesic system (con~nm~ng cnkcphalincrgic. rrotoncrgic. and nondrcnrqic pahw~n). All mdogcnous oplo~rb contin IJIC a,.,,,~ acid squrncc rrm,aw&on~ &rmr++.n, Idamtn~ Thry arc formed hv clcavagc 9‘ larger prccunor molctuln and can lx g -0.1pcd arcording~. Both mctaAcphalin and Icu+nkcphahn UC dcrirtl from procnkrphahn A Entcpha. lim mr ¶nmalolopiully laaliud IO arcu of the ccnurl nervous ryucm KISS) eurntial for antinociccpion. Thy UC l bo found in Lhc gaumintinal uacl. sympathetic ncrwxn 9% um. and adrenal medulla. &cndorphin is the most po~cn~ of rhc endogcnousopioiandisfoundmrhchvpcr thalrmus. periqueduc~l g-y maucr. and locus ccndcus. @aadorphm I) gcncnwd from clcangc of pro-op~omrlanotorcin and IS rclcased in a one-toanc molar ratio rrich xircnncortkotmpic honnonr (ACTH) from the pituitary. Dynorphin (IJIC prototypic ligand of the ai-cccptor) and a+wncodorphin am drnrrd from prodynorphin (procntcphalin-B). De@ having -totopk loalization simtiar to thaw of the mkcphahm. rhc dynorphinr pcum no ywrnt atu!g&c propmies.
opwld
Rfrrpfon
Opioib, produce their analgesic cllccl b mimlcking the actions of cndogcnous opioid pcpdc+ at spccdic rctcpton wilhm the CSS.’ The rcccp~or ran be viewed as a common molcculu site of action for a diwnc group of compounds. The receptor mediates IWO functions: chemical rccognilion and c~ologic action. Thaw functions arc locahrcd IO dilTercnt phnical areas of Ihc receptor complcr. Only Ic\orolrlon iwlncn posxss rnalg&c acwily and. chcrcforc. Ihc recognium ire b highly specific.” Binding finity r&n 10 the ww@ of auxhmcnt of chc opoid u) the rrcrpor iu. as opioids wall bind IO the recognition WC with varying strength.” It is posibk to dctcrmine lb rank order of binding affinitio using r-uiau hinmny spuna. R-u binding aBinL ties correlate quite clos.+y with the analgesic polcocio of the opioids.’
Thcrc
arc scvcral lvps of opioid rcccpton of nhirh mediate an arrav of pharmacologic cfiecu“” Mew opiolds hind to “morphineprcfcrring” or p-rcccp~orr hndorphin is rhc prototypic cndogcnous ligand. and morphine n the wototyic cxqcnous ligand. Using autoradiographv. prcccpton haw bcn found .n highconccnuatiom in an-u of the brain that mediate opioid-ioduccd analgesia Tbcsc areas include the pcriaqucducul pay. rhc m&us nphr magnus. and tJw medial chalamus.‘~” Other opioid rcccpcon Lhac pro&cc analgcsic cfkcu (b and r-rcccpton) are found mainly in Lhc spinal cord. While yrcccpron arc found a8 the Icvcl of the spinal cord, activation ol prrccpcoo ir ‘argcly rc5ponsiblr for wpraspinal analgea 730 subtypes of p-rctcpcon have hccn dcmtinsu-ated.““* Acthauon of )r,-rccepton
(Table
2). cwh
Vd
268
II No. 5 hfq
19%
AgonisLI Morphmc Me lidinr romorphonc d Oxymorphmc lnwphnnol Fenunyi Sufenunil Alfenonil Mclhadonc Agonirt-anogoniw Buprcnorphine Bwx-phanol
Nalbuphinc PrnuuKlnC fkmcLnc
Dynorphin is c)ar prototypic cndogcnous agw nist. Morphine also acts a a &agonist. However. the relative affinity of morphine for the r-receptor is 200 times less than its afFinity for the p-receptor. Analgesia attendant IO the opioid agonist-antagonists is mainly derived from r-rcccptor activation. In vitro binding studies in the rat vas deferens have described the c-receptor, though it is not well character&d. bndorphin is the prcl posed cndogcnous agonist. Ar Btndorphin is released in a one-tmnc molar ratio with ACTH from the pituitary gland, the c-receptor may mediate a hormonal effect of pndorphin. Another poorly characterized receptor that has been proposed as an opioid receptor in the past is the o-receptor. The agonistantagonist opioids at least partially activate the o-receptor, producing psychotomimetic effects including dysphoria and hallucinations. as well as tachycardia, tachypnca. and mydtiasis.
Inhittsic Ackdy: The &Uionsh$ Bduwn Rrwpx Binding and Responst The intensity of physiologic actions produced by exogenous administration of an opioid defines its intinsic activity. Agaictc pr* duce a maximal biologic response through receptor binding. Anfqnirlr (naloxcne) have low or no intrinsic activity and reverse or inhibit the effects of agonists by preventing receptor acccu.*s Padal agt3xisl.t produce a
submaximal response at the receptor even at high doses (e.g.. buprcnorphinc’s action at the p-receptor). Opioids can have divergent activities at different recepton, simuhaneously acting as an agonist at one and an antagonist at another. These opioids are termed ngonisl-cnfagoni& or m&d dgati*nlogonuf.~.“~~’ Pentazocine is a weak competitive antagonist at the yrcccptor, a strong rc-agonist. and a u-agonist. Nalbuphine rcvcrses opioid-mediated respiratory depression through p-receptor antagonism but analgesia through partial provides r-agonism. ” Table 3 lists the interactions of opioids at Mrious receptor subqpes. The agonist-antagonists also exhibit characteristic pharmacologic properties: (a) the slope of the dose-response curve is less steep than that of a full agonist (Figure 3); (b) the dosc-responsc curve exhibits a ceiling effect (i.e., a submaximal response as compared with a full agonist) (Figure S); and (c) concomitant administration of an agonlst-atttagonist and full agonist can reduce the effect of the full agonist.
The Gmqi#
of Equianalgaic
The “potency” or intensity cflcct of individual opioids upon: (a) access to the receptor.
Dosing of analgesic is dependent and (b) bind-
phenomenon suggests potency of some opioith repetitive dosing.”
The Oral lo Pamite&
Fig. 3. The cot8ccpt of intrinsic activity. Full agonists produce a maximal biologic responu (e.g.. analgc sia. respintory deprcsrion. etc.). while partial age nius produce ? submaximal response en at high doses. Antagonists
rcwry
the biologic
rqonsc
to
opioids. Tltcreforc. their effect is liied as zero in the figure. (From reference 62. witb Permission.) ing aflinity (“fir” at the receptor site). Access to the receptor for p-agonists is dependent upon physicochemical and pharmacokinetic properties: (1) partition coefhcicnr. (2) pKa, (3) the degree of ionization, (4) unbound fraction of a dose, (5) apparent volume of dis tribtttion, (6) clearance. and (7) the rotttc of administration. Therefore. apparent differences in potency among opioids are primarily the result of physicochemical and pharmacokinctic differences among individual opioids and not a function of pharmacodynamic dis tinctiotts. Thus. all opioids can be made quipotent or qttianalgesic by adjusting for phyicochcmictl and pharmzcokinctic differences by correcting for dosage and route of adminis uation. This concept is extremely important in the clinical use of opioidsnsn It is important to emphasii that quianalgesic convenion schemas can only he used as guidelines. Practitioners should not be dogmatic in their interpretation. as certain mcthodological problems are inherent in the genesis of such convenion tables.
hcomphc
Cross-Tokranu
Patients can become tolerant to the analgesic effects of a given opioid. In such cases, another opioid can be substituted to provide helter analgesia, as opioids exhibit incomplete crostolennce.“” Clinical exp-ricncc shows that onehalf of the qttianalgesic dose of the new optoid may be used for initial dosing. This
that may
Puncy
the relative increase with
mio
The bioavailabiity of otal morphine varies between 15% and 64%, with an average oml bioavaiiability of 3l3%.s’ Therefore, morphine has significant first pass metabolism. which must be taken into account when convening from oral i3 parcntetal adminisuatioc.” For acute pain and single doses, the oral to parentcnl potency ratio for morphine is 1:6.s’ For chronic pain and multiple doses, the oral to parcntetal potency ratio for morphine is I:2 or 1:3.s’-“-w These ratios have been empiticalty adopted for oral IO parcntctzt convcnion for otlwr opioids.
771~ ,#Cpivk oJ Potency Among Pamntmd Routes The intramuscular (IM). subcutaneous (SC). and intravenous (lV) routes of adminis ttation are assumed to be quipotenr in many conversion schemes, thereby assuming cquhalent bioavail&lity among the three routes of administration. Few data exist to validate this assumption. however. and several authon have questioned it. In a study by Urquhart and colIcagues.K patients receiving hydromorphone vka SC PCA had significantly higher dosage requirements in comparison to patients recciving lV PCA. thereby suggesting ttnqttal bto availability. According to Urquhart and colleagues,% the subcutaneous to intravenous potency ntio is l:1.5 or l:2.
RtspirafiAm All p-agonists and the partial agonist buprcnorphinc produce a dosedcpendent reduction in the responsiveness of brainstcm respiratory centers to increases in carbon dioxde tension (PC0,).“7-w This reduction in responrtveness t.s chatactcrized by an increase in resting PCOs and diplaccmcnt of the CO, response CUM 10 the tight.” Eqttianalgesic doses of p-agonists will produce a similar degree of respiratory depression and an quimlcnt shift of the CO, response curve to the righ~“~’ Opioid agonists also depress the
FtT?DWt
270
T&k opioid
E4phdgd
4 Dosing
gcsic dosages, opioids differ potential to produce slcep.ti
&pivaknoEqu;maFc*c
Opioid
ROUIC
Morphine
Paremetal or.4 PXenlCnl Old PUenlCnl oral RWltenl Oral Rrcntcral Oral Psrenteral Onl Parentcral 0-l Parcnterrl Onl
Cdeinc oxycodonc Lcvorphanol Hydromorphonc Meperidinc Methadone Fentanyl
IO 30 130 200 15 30
2
bid II No. 5 hia7 19%
mg mg mg mg mg mg
w
4 mg I .5mg 7.5mg 75 mg sm mg IO mg m w3 t.JdLLL
pontinc and medullary centers involved in regulating the rhythmicity of breathing. Depression of these centers results in pro longed apnea between breaths, delayed exhalation, and periodic breathing.s’.% Mixed agonist-antagonist opioids do not produce dose-related respiratory depression but exhibit a limited or “ceiling” effect.“’ Agonist*ntagonists displace the CO, response curve to the right, but the curve is chatacteristically “bclkhaped” when these opioids are given in increasing doses.” Changes in Cognition, Alerfneq and Mood Opioids cause alteration in mood. PaGents report feelings of warmth, drowsiness, and sometimes well-being or euphoria. Alterations in mood are believed IO be mediated through the limbic system.” At sttfhdendy high doses, opioids may cventually produce sleep. However, unconsciousness is not a certainty even it high or “anesthetic” doses. Arousal may still be produced by noxious stimulation’s Moreover, at quianal-
in their
intrinsic
Tolerance, Physical Ikpndence, and Addiclion Continued exposure of the receptor to high roncentrations of opioids can cause tolerance. Tolerance refcn to the progressive decline in potency of an opioid with continued use. so that increasingly higher concentrations are tcquired to achieve the same analgesic effect. The phenomenon is characteristic of opioids as a class of analgesics and is receptor mcdiated. When tolerance develops to a particular opioid. cross-tolerance to other opioids concomitantly develops, though such tolerance is incomplctc. Physical dependence does not in any way imply addiction. Physical dependence is a physiologic state characterized by withdrawal (abstinence syndrome) after discontinuation of the opioid. Yawning, diaphorais. lactimadon, coryza. and tachycardia arc the initial manifestations of the abstinence syndrome. Later, abdominal cramps, nausea, and vomiting occur and peak at approximately 72 hr. Tolerance to the opioid is quickly in*.t during withdrawal. Addiction is defined by the World Health Organization as: A sute. psychic and sometimes also phyical. resulting from the interactions between a living organism and a drug, characterized by behavioni and other responses that ahrap include a compulsion to take the drug on a continuous or periodic basis in order to expc ricncc its psychic cflccw. and sometimes to avoid the discomfort of its alxence. Tolcrancc
may or may not be present.‘” In the popular mind, addiction is a compulsion to obtain a drug in order to experience its psychic effects. The definition of the World Health Organization closely approximates such a conception. Once again, it is important to emphasize that addiction implies compulsive behavior and psychologic dependence. Tolerance (a pharmacologic property of a class of drugs) and physical dependence (a physiologic effect also characteristic of this class of drugs) are conceptually and phenomenologically distinct from addiction. Can administration of opioids iatrogenically cause addiction? A prospective study has examined the incidence of opioid addiction in 12.C00 hospitalized patients receiving at least
one dose of an opioid.* Only four reasonably welldocumented cases of subsequent addiction were demonstrated in patients without a prior history of drug abuse. Thus, opioid addiction may be a tare iatrogenic event, particularly when opioids are used to treat pain.”
Effects Ujmn the Gastroinhzstinal Tract The propulsive peristaltic contractions of both the small and large intestines are decreased by opioids. At the same time, the amplitude of nonpropulsive. rhythmic, segmental contractions is enhanced. In the upper gastrointestinal tract, opioids cause decreased gastric motility while increasing anttal tone. Wtth concomitant enhanced tone in the first part of the duodenum, delayed gastric emptying may result. Sphinctetic tone is increased by opioicb in th e pyloric and anal sphincten and ileocecal valve. Increased tmnsit time is produced by coupling decreased propulsive activity with enhanced sphinctetic tone. Constipation results from the delay in passage of intestinal contents. allowing for greater absorption of water, increased viscosity, and desiccation of bowel contents. The peripheral and central mechanisms underlying the effects of opioids upon bowel motility are unclear.” With respect to peripheral mechanisms, opioils affect choline@. serotonergic, and enkephalinergic receptors located in the myenteric plexus of the intes tine. With respect to central mechanisms, the effects of neutaxial administration of opioids are not inhibited by systemic ganglionic blocking agents or the removal of the extrinsic innervation of the bowel.‘” Moreover, injection of morphine into the cerebral ventricles inhibits bowel motility. huraventricular administration of naloxone or vagotomy can inhibit or revetse this effect” Thus, there is substantial evidence to suggest that both local and central mechanisms are involved in opioidinduced changes in bowel motility.
Biliary Tract p-agonists produce a marked increase in biliary tract pressure. Pressure within the common bile duct may increase tenfold after the subcutaneous injection of IO mg of morphine.” A much less marked increase in biliary pressure is seen after administration of agonist-antagonists.“’ Moreover, nalbuphine
has been reported to actively reverse sphincter of Oddi spasm. However, analgesia is still maintained (x-receptor analgesia).ss
Gudiova.uulur
Eflkcts
Opioids produce chronotropic. inotropic. and peripheral vascular changes. Opioids pro duce a dose-dependent btadycardia due to central stimulation of the vagal nucleus in the medulla.5’~5’ As the bradycardia is vagally mediated, it can be blocked with atropine.“s The exception to this phenomenon is the administration of meperidine, which may cause tachycardia. Meperidine is structutally similar to atropine. Negative inotropic effects may be produced by meperidine at doses as low as 2.0-2.5 mg/kg.5’55 Otherwise, opioids maintain normal myocardial contractility at clinically useful dosages. All opioids can reduce direct myo P but this effect cardial depression,“.“.s is often not seen even with anesthetic dosages. Morphine has both a direct effect on vascular smooth muscle and an indirect effect through the release of histamine. Arteriolar dilation and venodilation are thereby pro duced.Histamine release b belicved to be the primary mechanism underlying vasod&tion with morphine. Meperidine and codeine also release histaminz. Fentanjl and sufentand do not6’.ez
This brief review has described some of the salient characteristics of opioid drugs. The literature pertaining to opioid pharmacology is extensive and relevant to the clinical use of these drugs. Recent review are available and can provide rich detail about basic and applied considetations.‘““s’sc
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Vd 11 h’o. 5 My
272
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p opiate
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195%
Res 1978;153:205-
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of inuathecal
opi-
ML.
Knapp
Y White
PF. Patient-
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a compaim~ hydromorphone.
of inuavenola Anesthesiol-
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badvkg
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