CSF distribution of opioids in animals and man

Ada Anaesthesiol Srand 1987: 31, Supplementum 85: 38-46

CSF distribution of opioids in animals and man KICHARD PAYNE Departments of Neurology and Pharmacology, Memorial Sloati-Kettering Cancer Center, Cornell University Medical College, Ncw York, New York. USA

'l'hc CSF distribution of opioids alter subarachnoid administration is important in determining thcrapnitic and undesirable side-erects. Thcrc are many factors which influence CSF distribution of opioids including the age, position, anatomy of the spinal column of the patient or animal, and the physico-chemical propertics of the opioid solution and of the CSE: Opioids are cleared from their site of administration in CSF by thrcc mtdianisms: I ) uptake into thc spinal cord, 2) diffusion through the dura and uptake into the blood, and 3) rostral-caudal CSE' distribution. Physico-chemical Factors such as lipid solubility, degree of ionizatirm in thr CSF and the baricity of the opioid solution are important in determining the rate of clearance by tticst. three routes. Opioids whirh arc highly lipid soluble, have high affinity for delta and/or kappa opiate recc'por subtypes, and are largely non-ionized at physiologic CSF pH, would have optimal pharmacokinetic propcrtics for subarachnoid administration. 'I'hese properties would allow administration of a small dosc of opioid which would be rapidly taken up into thc spirlal cord, thercby limiting CSY and vascular distribution t o

supraspinal brain regions.

x;Y words: CSF; opioids; pharmacokinetics; subarachnoid.

Opioids injected near the spinal cord produce analgesia without concomitant sensory, motor or auto- nomic blockade (1-3). After spinal subarachnoid or epidural administration, narcotic analgesics and endogenous opioid peptides interact with opiate receptors in the superficial layers of the dorsal horn to suppress transmission of nociceptive impulses (1-5). Most active arc those agonists which have high afinity for delta and kappa opioid receptors (6). Opioids reach their sites of action in the dorsal horn of the spinal cord either by diffusion from the CSF or by uptake into the posterior radicular artery (4).

There are three routes tor clearance of opioids after administration into the CSF: 1) local uptake into the spinal cord since CSF communicates directly with the spinal cord interstitial space (7, 8); 2) movement in the rostral-caudal CSF axis (9-1 I ) , and 3 ) transdural penetration with vascular absorption and redistribution (4, 12). The selectivity of eKect of spinal opiate administration relates to these competing influences. There are several factors which determine which route will predominate. Among the more important are the physical characteristics of the CSF and of the opioids administered into the CSF, the technique of injection (including the volume, rate and force of injection), and the position and anatomy of the spinal column of the patient or subject (13).

This review summarizes factors influencing the CSF distribution of opioids in animals and man after intrathecal administration, and attempts to correlate rostral CSF movement of opioids with therapeutic and undesirable side-eKects.

FACTORS INFLUENCING CSF DRUG DISTRIBUTION At least 25 factors potentially influence drug distribution in the CSF (13). These factors have been stud- ied extensively with local anesthetic administration, and most if not all of the same factors are applicable to opioids as well (see Table 1). Importarit P actors include: 1) patient characteristics (age, height, weight, configuration of the spinal column), 2) thc tcchniquc. of injection (direction of the needle, type of nccdlc, rate and turbulence induced by the irijection), 3 ) characteristics of the CSF, including its density, baricity and circulation, and 4) characteristics of the solution to be injected, including its density, volume and concentration (13). Since the hypothetical and actual influence of these factors have been extensively discussed (13-20), this review focuses on those physicochemical characteristics of opioids which influence CSF drug distribution, on the mechanisms of C S I movement in the spinal subarachnoid space and on the influence of these factors on CSF drug distribution. These factors are probably clinically relevant in pre- dicting which opioids have optimal pharmacokinctic properties to maximize therapeutic and minimiLe toxic effects after epidural or subarachnoid administration.

CSF DISTRIBUTION OF OPIOIDS AFTEK SUBARACHNOID ADMINISTRATION A. Movement of CSF in the spinal .subarachnoid ace A majority of the CSF is secreted by the choroid plexi

CSF DISTRIBUTION OF OPIOIDS 39

'Iahlc I Some Ihi~iors iiillucnring CSF distribution of opioids after subararh- iioid atlrriiniatratioii.

l'atiziic characteristics 1 . Age. sex and height 2. Iiier;r-;il~d~iminaI/thoracic prcssure 3. An,i(omic configuration of spinal column 4. 1'11sici1m during and after injection

'l'echiiirluc. and site of injection 1 . K.III. (if in,jcctioii 2. '1'iirliirlriic.c of injertion (harhotagc) 3. Siec ol'irijccrion (ventricular vs. subarachnoid)

Charxtcristics of the CSF I . l k i i + i t y 2. B;tricic) 3 . Lipid siilu1)ility 4. I h w 1 1 1 opioid 5. Volume of opioid solution 6. ~asoc.oiistri(,tors*

*Applies to epidural injections. Modilicd lrom Grccnr N M , A m l h Analg 1985: 64: 715-730

in the cerebral ventricles and moves in a cranial- taud'tl direction (21-24). The rate of CSF secretion varies from 0.35 ml/min (500 ml/day) in man, to 0.002 ml/min (3 ml/day) in the rat, but the rate of CSF secretion as a fraction of the weight of choroid plexus is relatively constant among species and is about 0.2-0.3 pl/min/mg choroid plexus (23-25). The total volume of CSF in man is about 150 ml, and approxi- matcly 50°, of the volume is in the spinal subarachnoid \pace 123). Bulk absorption of CSF occurs via arachnoid granulations located in the cerebral sinuses and to ii lesser extent in the spinal subarachnoid space (7, 23, 24, 26). A net turnover of spinal CSF occurs becauw of cranial secretion, spinal and cerebral reab- sorption.

Although there is evidence for a spinal circulation of CSF in the cat (27) , the evidence for formation of CSF in the spinal subarachnoid space or for a spinal CSF circulation is controversial in other species, including man (23, 24, 28-30). The mechanism of bulk movement of spinal CSF in a cranial direction is un- clear, but changes in transabdominal and transtho- rack pressures and turbulence produced in the CSF b y iriiec lions of solutions with volumes exceeding 10% of the spinal CSF volume are important factors (20, 21 , 23, 31). The cranial movement of colored dyes and r'rdiolabeled tracers introduced into the spinal subarachnoid space is dependent on these factors (18, 21, 24, 31, 44).

The physical characteristics of CSF may be an important determinant of CSF drug distribution. The densitj, specific gravity and baricity of CSF are similar but ndt identical to water (13). The baricity of a

solution is defined as the ratio of the density of the solution (g/ml) divided by the density of CSF (which is 1.0003 g/ml a t 37°C). The baricity of CSF is 1.00 by definition (32, 33). The CSF distribution of hypo- (< 0.9990) or hyperbaric (> 1.0015) solutions is influ- enced by the position of the patient or subject, whereas isobaric solutions are not (13, 32-35).

The physical characteristics of the solution injected into the subarachnoid space are equally important determinants of their CSF distribution. Although there is much information relating the density, concentration, amount, baricity and volume of anesthetic solution to the spread of such solutions in CSF, similar data are lacking for opioid solutions (4, 13). Epineph- rine may influence the CSF distribution of spinal opiates, particularly after epidural administration (36). The vasoconstriction produced by epinephrine appears to reduce vascular clearance of drug from the epidural space, and indirectly increases CSF drug concentrations (36).

Acute and chronic administration of opioids in animals and man do not appear to cause spinal cord or meningeal toxicity (37, 38). The pH opioid solution injected intrathecally is usually more acidic than CSF. The administration of morphine and methadone solutions (with p H 4.78 and 5.73, respectively) decreases CSF pH by 0.1-0.2 pH units, but there is no associated increase in CSF turbidity (39). The only opioids thus far shown to increase CSF capacity, presumably as a result of precipitation of CSF proteins, are opium and heroin, in high doses (4, 39). With the above excep- tions, CSF pH, protein and cellular compositions are unimportant determinants of drug distribution (13, 23).

B. CSF opioid concentrations and pharmacokinetics 1 . Single bolus administration in animals and man. In man, the direct administration of morphine and other opioids into the CSF produces concentrations 2 or 3 orders of magnitude higher than can be achieved by systemic administration (9, 40-42). Since there is 1 OO(/, bioavailability and no absorption phase after intrathecal administration, peak levels are achieved at the time of injection. The elimination of opioids from CSF is biexponential and dependent on lipid solubility (9, 10, 43). For hydrophilic opioids such as morphine and D-ala2-D-leu5 enkephalin (DADLE, a stable ana- logue ofleucine enkephalin, with a molecular weight of approximately 569), mean elimination half-lives were 94-1 15 min, respectively (10). The mean CSF clearance of morphine and DADLE is also similar at 0.54 and 0.27 ml/min, respectively (10). For diacetylmor- phine (a lipophilic opioid) the elimination half-life is less than 10 min (43). Useful physicochemical and

40 R. PAYNE

pharmacokinetic parameters of a number of commonly used opioids are listed in Table 2.

Opioids may be distributed rostrally in the CSF. In man, the lumbar subarachnoid administration of 2 mg of morphine-sulfate is associated with cervical CSF levels ranging from 2035-4900 ng/ml at 60 min, docu- menting significant rostral CSF spread of morphine

Using a sheep preparation in which the lumbar subarachnoid space and cisterna magna are cannula- ted, i t has been demonstrated that the rostral-caudal movement of opioids within the CSF axis is dependent on lipid solubility of the compound and bulk flow movement of CSF (1 1) . After the administration of a 200 pl “cocktail” containing, 1.0 mg morphine, 2.0 mg methadone and 3.8 pCi C-14 sucrose into the lumbar subarachnoid space (this volume represents < 2% of the spinal CSF volume in sheep), continuous cisternal CSF samples are collected over a 5.6-h period using a ventriculo-cisternal perfusion. Morphine-sulfate and methadone-hydrochloride are used as repre- sentative hydrophilic and lipophilic opioids, respectively (see Table 2) . Sucrose is a hydrophilic molecule with a CSF clearance of less than 20& after a 6-h spinal subarachnoid infusion, and is thus used as a non- absorbable marker of CSF flow (28). The animal is maintained in a sling to minimize body movements that might displace spinal CSF, but is not anesthetized. Morphine and C-14 sucrose appear and peak simultaneously in cisternal CSF at 90 min after lumbar subarachnoid administration (1 1) (Fig. 1). Metha- done is not detected in cisternal CSF within the 5.6- h collection. Furthermore, the movement of morphine is associated with its clearance from CSF since the ratio of C-14 sucrose/morphine is, on the average, 7- fold higher in the lumbar CSF as compared to the cisternal CSF (1 1 ) . Methadone was completely cleared before it reached the cisternal CSF ( 1 1 ) . This differen- tial rostral-caudal CSF distribution and clearance of morphine and methadone has been observed in man as well (9).

The time course of appearance of morphine and C- 14 sucrose in rostral CSF sites observed in the human

(9).

- RP-26

DOSE INJECTED AT T=O 70

60 B . 50 9 40

g 30

Y 2 10 - 0

0 2 0 mg = 2 x lO3pg 1 0 mg = 1 0 x l o 3 pg -

A 3 8 pCI = 8 5 X 106 dpm

E

+ 20

Q

50 100 150 200 250

0 2 0 mg = 2 x lO3pg 1 0 mg = 1 0 x l o 3 pg

A 3 8 pCI = 8 5 X 106 dpm

9 40

Y 2 10 - 0 Q

50 100 150 200 250

‘lhble 2 Phvsico-chemical and pharmacokinetic properties of commonly used opioids.

Time (mins)

Fig. 1. Cisternal CSF concentration of C-14 sucrosc, morphine arid methadone after lumbar subarachnoid administration. Cisternal CSF is collected by ventriculo-cisternal perfusion. C- 14 sucrose and morphine appear and peak simultaneously in cisternal CSF a l 90 min after lumbar administration. Methadonc is completely clcarcd f‘roni CSF before reaching the cistrrna magna.

and animal studies can best be explained by bulk flow movement of CSF. I t has been demonstrated that injection of radiolabeled tracers and radiopaque dyes into the lumbar subarachnoid space at < 100/, of the spinal CSF volume is associated with their appearance in basal CSF cisterns within 1 h, and within the cerebral ventricles within 4.5 h (21, 22, 31, 44). Thc appearance of morphine and C-14 sucrose in the cisternal CSF at 90-190 min in the sheep is consistent with other experimental observations of cranial movement of tracers in CSF (31, 32, 44, 46). It is also consistent with studies of cranial opioid movement in man (9) and clinical studies which have ohserved the appearance of respiratory depression 1-4 h after intrathecal morphine administration (1, 4, 47, 48).

Bulk flow rostral movement of morphine and C-14 sucrose with the CSF appears to be the best expla- nation for the pharmacokinetic data observed in the human and animal studies. No other potential mechanisms of drug movement in the CSF axis such as: 1 ) diffusion within the CSF, 2) vascular redistribution to the cisterna magna via systemic absorption, or 3) movement up Batson’s perivertebral plexus, can ex- plain the time course or large concentrations of opioids observed in cervical or cisternal CSF after lumbar

~ ~~ ~

Opioid Molecular Wright Pka b * P Cord CSF rdtio yo Uptake into cord References

Morphinr 285 7 9 -5 00 0 060 3 8 4,41,69,94,95 H ~ d i umorphont 285 8 05 -5 00 0 061 3 9 69,93,94,95 Lt vorphdnol 258 9 37 - 2 04 - 69,94,95 hft pt.ridine 247 8 5 0 53 - 4,41,94,95 Methadont 247 9 3 165 3 1 67 0 4,69,94,95 Irnuriyl 336 8 4 129 34 7 95 8 4,41,69,94,95

*Log or hrptane/pH 7 bun‘er partition coefficient.


subarachnoid administration. Diffusion of compounds over the 70-90-cm lumbar subarachnoid-cisterna magria distance in the sheep would require many days rather than minutes (49). Prior studies with this sheep model have demonstrated that the “flux” or movement of morphine from the plasma to cisternal CSF is small after intravenous infusion (1 1, 50). In man, during the continuous intrathecal infusion of morphine to steady state, plasma levels of morphine were 3 orders of magnitude lower than the CSF (10). Therefore the very high cisternal CSF morphine concentrations seen after subarachnoid administration could not be accounted for by vascular redistribution of small plasma concentrations observed after intrathecal administration in the sheep ( < lng/ml) or man ( < 20 ng/ml; see references 10, 1 1, 50). Lastly, movement of opioids up Batson’s plexus (which is a valveless peri-vertebral venous conduit allowing direct communication of pel- vic veins with the great veins of the head), has been postulated to account for the immediate onset of retch- ing and vomiting in cats which may occur after epidural administration of opioids (12, 64). The 1.6-h time course of opioid movement in CSF observed in the animal and human studies is thus inconsistent with rapid movement up Batson’s plexus.

P-cndorphin is also cleared from CSF in a manner consistent with bulk flow (51). P-endorphin is a 31 amino-acid peptide with a molecular weight of 3300 and poor lipid solubility. It is a potent analgesic when given intrathecally to animals and man (52-56). Lee ct al. (51) compared the CSF distribution of P-endorphin to C-14 inulin. Like sucrose, insulin is an inert marker which is cleared from the CSF entirely by bulk flow absorption through the arachnoid granulations (24, 57). After lumbar intrathecal administration in the rhcsus monkey, C-14 inulin and P-endorphin are cleared from CSF in a nearly identical time-course (51). This suggests but does not prove that bulk flow absorption in CSF is the main route of elimination for P-endorphin (5 1, 52). Enzymes capable of degrading enkephalins and endorphins have been identified in the CNS but not within the CSF (51, 58, 59, 96), so that enzymatic degradation is not a likely mechanism for P-rndorphin’s elimination from CSF.

2. C‘onlinuous subarachnoid infusion of opioids in man. Con- tinuous infusion of opioids into the subarachnoid space offers the advantage of maintaining steady-state drug concentrations in the CSF (10, 60, 61, 81). Moulin et al. infiised morphine and DADLE enkephalin intrathecally at Tq 10 and Ll-2 in two patients with chronic cancer pain (10). They noted that the intrathecal infusion of morphine in the upper lumbar spine, in doses r’anging from 18.2-39.2 pg/min was associated

with L2-3 steady-state CSF levels of 110-213 pg/ml after 72 h (10). The corresponding cervical CSF levels were 14.33 pg/ml, indicating a 7: 1 lumbar/cervical CSF ratio. In a second patient given subarachnoid morphine infusions of 10.4-31.3 pg/min a t T g - , O , the ratio of lumbar to cervical CSF concentrations was only 2:l (10). This indicates that the site of drug administration is an important determinant of the lumbar to cisternal concentration gradient (10). Fur- thermore, increasing the infusion rate %fold produced a 2.3-fold increase in CSF morphine levels, indicating linear kinetics even at high CSF concentrations ( lo) , and suggests that one can reliably increase the intrathecal infusion rate of morphine and predict the corresponding CSF concentrations.

DADLE administered by single bolus intrathecal injection in animals (62) or man (92) produces analgesia. Intrathecal DADLE administration in man produces analgesia and side-effects similar in quality and duration to intrathecal morphine administration (92). Yaksh has demonstrated a very limited cross-tolerance between intrathecal DADLE and morphine in animals (6, 62). DADLE has been administered by continuous infusion in man as well (10, 63). The physicochemical properties of DADLE are not well known, but studies by Moulin et al. suggest that its pharmacokinetic properties are similar to morphine (10). The continuous infusion of DADLE at TSlo at rates of 0.63-1.40 pg/min in an opiate-tolerant patient, was associated with steady-state lumbar CSF concentrations of 1.2-1.8 pg/ml and cervical CSF concentrations of 0.5-0.8 pg/ml after 48 h (10). The lumbar/cervical CSF ratio was approximately 2:1, the same as morphine’s ratio when administered in the same patient at T9-15 10 (10). In addition, the clearance of DADLE was approximately 1 ml/min and was similar to that calculated for morphine (10). Thus DADLE has a CSF pharmacokinetic profile very similar to morphine, which is characterized by slow clearance and rostra1 ascent in the spinal CSF axis after lumbar and thoracic subarachnoid administration.

DRUG MOVEMENT F R O M CSF TO BLOOD Opioids administered into the subarachnoid space may be cleared from CSF into blood by movement through the dura and/or spinal arachnoid granulations and uptake into epidural veins, which are in close proximity (4, 10). There are two venous circu- lations near the epidural space, but only one communicates directly with the intracranial vasculature (64). Uptake of opioid into Batson’s plexus provides a means by which drugs may reach supraspinal CSF sites immediately after administration (12). Uptake of

42 K. I’AYNE

opioid into the inferior vena caval system, however, will provide systemic circulation (4, 65). Spinal opioid administration is associated with measurable levels of opioids in the systemic circulation (9, 10, 40, 41, 65). Iritrathecal injection of 0.25 and 0.5 mg morphine provides plasma levels of 1 ng/ml or less, which were sustained for up to 5 h (40, 41). In another study, plasma morphine concentrations were compared after intramuscular, epidural and subarachnoid administration of 0.2 mg/kg morphine-sulfate (65). The rate of vascular absorption was slowest after intrathecal administration as compared to intramuscular and epidural administration (65). Peak plasma concentrations of 50-60 ng/ml of unmetabolized morphine occurred about 15 rnin after intramuscular or epidural adrninis- tration (65). In contrast, after intrathecal administration plasma morphine concentrations peaked at about 26 ng/ml approximately 1/2 h later, and remained constant until 4 h after injection, at which time they exceeded plasma levels obtained from intramuscular and epidural administration (65). Therefore, the CSF- blood interface provides another route of drug clearance from the CSF, and may allow opioids to be delivered to supraspinal sites of action after subarachnoid administration.

DRUG MOVEMENT FROM CSF INTO SPINAL CORD Opioids may enter the spinal cord from the CSF by difl’usion through the pia-glial membrane or through perivascular Virchow-Robin spaces (7, 8). The spinal cord interstitial space communicates with the CSF, and there is free exchange of small ions, solutes and even drugs from CSF to the spinal cord (7, 23, 24). For example, the application of penicillin to the spinal cord surface produces epileptic, discharges, just as it does when applied to the cerebral cortical surface, suggesting that it is permeable to the CSF-spinal cord barrier (7 , 66, 67). Further, the application of radiolabeled morphine or fentanyl to the surface of the cord is associated with radioactivity in the substantia gelatinosa, which is concomitant to a significant suppression of lamina V neurons discharges evoked by peripherally applied noxious stimuli (4). This is pre- sumed to be a major mechanism of action of spinal opioids in the production of analgesia (3, 68). It does appear that opioids may reach the spinal cord by diffusion from CSF, although the time course of the accumulation and elimination of opioids from CSF into the spinal cord needs quantitation. For example, Bullingham et al. calculated theoretical values for distribution of opioids between the spinal cord and CSF (69), and concluded that the percentage of the initial

dose of intrathecally administered opioid taken up into the spinal cord was related to lipid solubility. This percentage was about 4% for morphine and >95(>” for very lipophilic compounds such as fentanyl (69). It should be possible to confirm these calculations by in uiuo techniques such as quantitative autoradiography, and to relate the time course of uptake and elimination and regional spinal cord and brain concentrations of opioids to analgesia and other pharmaco- logical effects after intrathecal administration.

RELATIONSHIP O F DRUG MOVEMENT IN AND F R O M CSF TO PHARMACODYNAMICS 1. Analgesia Hydrophilic opioids such as morphine, hydromorphone, DADLE and endorphin have significant rostral CSF distribution after intrathecal administration (9-11, 51). In addition, they penetrate the dura and spinal cord more slowly than do lipophilic opioids (69, 91). They are absorbed into epidural veins, providing systemic blood levels which may then be redistributed to analgesic sites in the brainstem (9, 10, 65). The interaction of supraspinal analgesic sites with spinal analgesic sites produces synergistic effects in animals (70), although this has not been proven conclusively in man. It is clear, however, that behavioral analgesia in animals can be achieved by opioid action limited to the spinal cord ( 1 , 2 ) .

It is not clear if supraspinal analgesic sites are re- quired for the production of analgesia in man (4, 40, 41, 71, 72). Crawford introduced a “hyperbaric” solution of morphine ( 2 mg in 6(y0 dextrose) into thc lumbar subarachnoid space and reported that he could not produce analgesia in an obstetric patient (71). Reasoning that analgesia was not achieved because the hyperbaric solution retarded rostral CSE’ movement of morphine, Crawford suggested that supraspinal sites must be activated for clinically significant analgesia in man. It is possible, however, that the position of the patient did not allow opiate receptor blockade a t the appropriate spinal level necessary to provide analgesia. Moreover, lipid-soluble opioids such as methadone, meperidine, and fentanyl probably have limited CSF rostral distributions (9-1 1 ) and yet produce profound analgesia by the spinal routr (82-87). Although these opioids would be expected to produce higher blood levels than hydrophilic compounds (e.g., morphine) when given intrathecally, the plasma levels are generally less than the minimum effective plasma levels necessary to provide analgesia in i.v. patient-controlled analgesia studies (4, 89). It is therefore unlikely that circulating plasma levels of opioids are the major cause of analgesia seen after


intrathecal administration. Thus supraspinal opioid redistribution via CSF and the plasma may potentiate spinal analgesia, but is unlikely to be the predominant site of analgesia in man (4, 40, 41).

2. Toxic eJfects Spinal opiate administration is associated with nausea, vomiting, sedation, urinary retention, respiratory depression and pruritis (1, 4, 73-78). The incidence of these effrcts varies from series to series, and with the possible exception of urinary retention, appears to be related to rostral spread of opiates in the CSF ( I , 4, 74, 88). Respiratory depression is the most important since it is a cause of fatality in the postoperative setting, and will be discussed separately.

a. Non-respiratory. The appearance of nausea, vomiting and pruritis has been correlated with the ascending spinal level of analgesia as determined by pin-prick after epidural morphine administration (88). The appearance of these effects has been postulated to relate to asceiision of morphine in the CSF axis, although this has not been directly demonstrated (88). The administration of epinephrine with epidural morphine may increase the incidence of these effects (36). This may occur because epinephrine decreases vascular absorption of opioids from the epidural space, thereby indirrctly increasing CSF opioid concentrations by increasing the gradient for CSF absorption.

b. Respiratqy. Respiratory depression may occur within 6 h after as little as 0.4 mg of morphine administered into the lumbar subarachnoid space (4, 47, 48, 76-78). The onset can be delayed up to 10-11 h and the duration may be as long as 18-24 h after intrathecal administration (48). This time course is slightly longer but nonetheless consistent with the passive cranial movement of radiotracers and metrizamide from the lumbar subarachnoid space to the basal cisterns and lateral ventricles (21, 22, 31, 44, 45). The plasma concentrations of opioids observed after intrathecal administration are unlikely to be large enough to cause respiratory depression, but may potentiate it (50, 77). It is of interest that the time course of respiratory depression following epidural morphine administration is similar to intrathecal administration, suggesting that rostral bulk CSF movement is the critical mechanism of respiratory depression following either route of spinal administration (4, 74, 88).

Respiratory depression following intrathecal administration has been reported more commonly with morphine than with other opioids, occurring in 5% of 90 patient3 receiving intrathecal opioids in one study (1, 73, 75) . This is so because morphine is more commonly

used than any other opioid, and its hydrophilic nature allows significant rostral CSF redistribution. However, respiratory depression has also been observed after intrathecal methadone (82) and meperidine (90). Respiratory depression has been observed after administration of hyperbaric morphine solutions, although the position of the patient may have favored rostral displacement of CSF (79). The factors which predis- pose to respiratory depression after intrathecal administration are: 1) old age, 2) lack of opiate tolerance, 3) presence of other CNS depressants, including general anesthetics, barbiturates, benzodiazepines and parenteral opioids in the postoperative period, 4) use of a hydrophilic opioid, 5 ) use of a large dose of opioid, and 6) large changes in thoraco-abdominal pressures, such as might occur with artificially ventilated patients (4). The first three factors relate to patient sensitivity to opioids; factors 4-6 all increase the chance of rostral CSF spread of drug. The position of the patient may influence the development and intensity of respiratory depression, but the sitting position does not protect against its occurrence (80). To date, deaths from respiratory depression have occurred only in the postoperative setting (1). The lack of opiate tolerance and the effects of anesthetic agents and parenteral opioids undoubtedly contribute to lethal respiratory depression in the postoperative population (4).

SUMMARY AND CONCLUSIONS Intrathecal narcotics produce profound, clinically useful analgesia, although adverse effects related to rostral CSF redistribution may occur. Physico-chemical characteristics of the CSF, the opioid administered, and the position of the patient are important determinants of drug distribution in the CSF. The physicochemical and pharmacokinetic properties of the opioid are particularly important for determining the therapeutic and undesired side-effects which occur after intrathecal administration. The pharmacokinetic properties of the optimal intrathecal opioid that would produce a selective spinal effect are:

1. High lipid solubility to allow rapid uptake of the drug from CSF into the spinal cord and cause quick onset of action (91). Since a large fraction of a lipid soluble drug is taken up into the spinal cord (69), the amount of drug available for rostral CSF redistribution or vascular absorption is small, thus limiting the effect to spinal analgesic sites (1 1).

2. Delta or kappa opiate receptor specijkty. Since spinal opiate receptors bind delta and kappa opioid agonists with high affinity (6, 62), one could theoretically ad-

44 R. PAYNE

minister a smaller dose of a selective agonist (e.g., DADLE) than a “non-selective” agonist (e.g., morphine) to produce comparable effects (6, 62, 95). Ad- ministration of a smaller (but more potent) intrathecal dose would decrease CSF and plasma drug concentrations and minimize effects at supraspinal analgesic sites activated as a result of vascular or CSF redistribution of the opioid. Delta or kappa receptor selectivity alone is not sufficient to produce selective spinal effects, however, since a “hydrophilic” delta agonist (DADLE) was associated with supraspinal redistribution and side-effects similar to morphine (10). This illustrates the importance of CSF distribution in the production of toxic and therapeutic effects, even with a relatively selective opioid agonist.

3. Metabolism in the systemic circulation. This property would be important to limit or eliminate the influence of systemic vascular redistribution to activation of supraspinal analgesic sites. Theoretically, if one could administer a delta- or kappa-receptor-selective, lipid- soluble opioid peptide intrathecally that was metabol- ized by enkephalinases upon absorption into the systemic circulation, one would have limited CSF and no plasma drug distribution.

4. Largely non-ionized in CSF at physiological pH. The normal CSF pH is 7.3 in animals and man (23). Opioids which are largely non-ionized at this pH would penetrate the lipophilic spinal cord more ef- ficiently than ionized opioid compounds. As can be calculated from the Henderson-Hasselbach equation, opioids with a pKa of approximately 5 would be largely non-ionized at a CSF pH of 7.3. However, the commonly administered opioids are weak bases with pKa’s ranging from 7.9-9.3 (see Table 2), and are thus largely ionized at normal CSF pH.

Future clinical and laboratory research should be directed at developing opioids with the above characteristics and quantitating the uptake of opioids from CSF into the brain and spinal cord. This is possible using quantitative autoradiography techniques, and may allow one to correlate regional tissue concentrations of opioids in CNS sites with plasma and CSF drug concentrations and in vivo effects. This will allow more reliable predictions of therapeutic and adverse responses to a given dose of intrathecal opioid in the individual patient.

ACKNOWLEDGEMENTS I thank Drs. J . Posner and C. E. Inturrisi for review of this manuscript. I thank Mary Callaway for assistance in preparation of the manuscript. This work was supported in part from grants from The

Robert Wood Johnson Foundation and the American Canrrr Soricty (1N.I 14).

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Yaksh T L. Spinal opiate analgesia: characteristics and principles of action. Pain 1981: 11: 293-346. Yaksh T L, Rudy T A. Analgesia mediated hy a dirrct spinal action of narcotics. Science 1976: 192: 1357-1358. Kitahata L M , Collins J G. Spinal action of narcotic analgesics. Anesthesiology 1981: 54: 153-163. Cousins M J, Mather L E. Intrathecal and epidural adrninistra- tion of opioids. Anesthesiology 1984: 61: 276-3 10. Atweh S F, Kuhar M J. Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla. Brain Res 1977: 124: 53-67. Yaksh T L. Multiple spinal opiate receptor systems in analgesia. In: Kruger L, Liebskind J C, eds. Advances in pain research and therapy, vol. 6. New York: Raven Press, 1984: 197-215. Somjen G G. Spinal fluids and ions. In: Davidoff R A, ed. Handbook of the spinal cord, vol. 1. New York: Marcel Dekkrr,

Somjen G G. Neuroglia and spinal fluids. J Exp Hi01 1981: 95:

Max M, Inturrisi C E, Kaiko R F, Grabinski P Y, Li C H, Foley K M. Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in cancer pain patients. Clin Pharmacol 7her 1985: in press. Moulin D M, Inturrisi C E, Foley K M. CSF pharmacokinetics of intrathecal morphine sulfate and D.ala.D.leu enkephalin in cancer patients with pain. Ann Neurol 1986: 20: 218-222. Payne R, Inturrisi C E. CSF distribution of morphine, methadone and sucrose after intrathecal injection. Life Sci 1985: 37:

Yaksh T L. The principles behind the use of spinal narcotics. In: Bullingham RES, ed. Clinics in anesthesiology, vol. 1, Phila- delphia: W B Saunders. 1983: 219-232. Greene N M. Distribution of local anesthetic solutions within the subarachnoid space. Anesth Analg 1985: 64: 715-730. Greene N M. Uptake and elimination of local anesthetics during spinal anesthesia. Anesth Analg 1983: 62: 1013-1024. Smith T C. The lumbar spine and subarachnoid block. Anesthesi-

Kitahara T, Kuri S, Yoshida J. The spread of drugs used for spinal anesthesia. Anesthesiology 1956: 17: 205-208. Kalso E, Tuominen M , Rosenberg P H. Effect of posture and some CSF characteristics on spinal anesthesia with isobaric 0.51yn bupivacaine. Br J Anaesth 1982: 54: 1179-1 184. Grundy H F. Movement of a dye in the spinal subarachnoid space. J Physiol 1960: 153: 59P. Hopkins E L, Hendricks C M, Cibils L A. Cerebrospinal fluid pressure in labor. A m J Obstet Gynecol 1965: 93: 907-916. Dubelman A M, Forbes A R. Does cough increase the spread of subarachnoid anesthesia? Anesth Analg 1979: 58: 306-308. di Chiro G. Observations on the circulation of the cerebrospinal fluid. Acta Radio1 Dzagn 1966: 5: 988-1002. di Chiro G. Spinal descent of cerebrospinal fluid in man. Neurol-

Fishman R. Cerebrospinal fluid in diseases of the nervous systrm. Philadelphia: W B Saunders, 1980: 6-54. Davson H . Physiology of the cerebrospinal fluid. London: Churchill-Livingstone, 1967. Evans C A N, Reynolds J M, Saunders N R, Segal M B. ‘I‘hc development of a blood-brain barrier mechanism in fortal sheep. 3 Physiol 1974: 238: 371-386.

1983: 329-380.

129-133.

1137-1 144.

ology 1968: 29: 60-64.

ogy 1976: 26: 1-8.

CSF DISTRIBUTION O F OPIOIDS 45

26. Chintz D G, Potts G, Deonarine V. Arachnoid granulation of the sherp. Arch Neurol 1974: 30: 169-175.

27. Grundy H F. Circulation of cerebrospinal fluid in the spinal rcgiirn of the cat. 3 PhyJiol 1962: 163: 457-465.

28. Kcssler J A, FcnstcrmachcrJ D, Owens E S. Spinal subarachnoid perliision of rhesus monkey. A m 3 Physiol 1976: 230: 614-618.

29. Stat 0, Asai T, Amano Y, Hara M, Tsugane R, Yagi M. Extra- ventricular origin of cerebrospinal fluid: formation rate quantita- t i d y measured in the spinal suharachnoid space of dogs. 3 . , V ~ u r ~ i w g 1972: 36: 276-282.

30. Lux W E. Fenstrrmacher J D. Cerebrospinal fluid formation in vrntrirlrs and spinal suharachnoid spare of the rhesus monkey.

31. Ricsclbach R W, di Chiro G, Friereich E J, Kall D D. Subarach- noid distribution of drugs after lumhar injection. N Engl3 Med 1962: 267: 1273-1278.

32. Davis H. Variability of cerebrospinal fluid density. Anesth Analg 1982: 61: 803.

33. Davis H, King W K. Densities of common spinal anesthetic solutions at body temperature. Anesthesiolou 1952: 13: 184-188.

34. Davis H, King W R. Densities of cerebrospinal fluid of human brings. Anesthesiohgy 1954: 15: 666-672.

35. Lrviii E, Muravrhick S, Gold M I. Density of normal cerebrospinal fluid and tctracaine solutions. Anesth Analg 198 1: 60:

36. Bromage 1' R, Camporesi E M, Durdnt P A, Nielsen C H. Inllucnce of epinephrine as an adjuvant to epidural morphine.

37. Aljouleish E, Barmada M A, Nemoto E M, 'lung A, Winter P. Acutc and chronic facts of intrathecal morphine in monkeys. 3 AnavJ/h 1981: 53: 1027-1036.

38. Wang J K. Analgesic effect of intrathecally administered mor- phinc. Re2 AneJth 1977: 4: 2-3.

39. Boriicr U. Muller H, Stoyanov M , Hempelmann G. Epidural opiatt! analgesia EOA: compatibility of opiates with tissue and CSF. In: Yaksh '1' L, Muller H, eds. Spinal opiate analgesia: rxp,criniental and clinical studies. Berlin: Springer-Verlag, 1982: 9 17.

40. Nordbcrg G. Pharmacokinetic aspects of intrathecal morphine an;rlgesia. Airesthe~ioloyy 1984: 60: 448-454.

41. NordIxrg C. Pharmarokinetir aspects of spinal morphine analgesia. h a AnaeslheJid Scand 1984: 28: Suppl 79: 1-38.

42. Jorgciisrn B C, Andersen H B, Engquist A. CSF and plasma nitrrphinr after epidural and intrathecal application. Anesthesiol-

43. M(rore A, Bullingham R, MrQuay H, Allen M, Baldwin D, (hlr A. Spinal fluid kinetirs ofmorphine and heroin. Clin Pharma- L O / 'Ihrr 1984: 35: 40-45.

44. Enzmiin 1) R, Norman D, Price D C, Newton 'I A. Metrizamine and radionuclide cisternography in communicating hydrocepha-

45. Drayvr B, Rosenbaum A E. Studies of the third circulation: arnpipaquc CT cisternography and ventriculography. ,j' Neuro- ru7g 1978: 48: 946-956.

46. Sage M R. The kinetics of water-soluble contrast media in the central nrrvous system. A~7NR 1983: 4: 8977906.

47. Davits G K, Tolhurst-Cleaver C L, James T L. Respiratory deprtwioii after intrathecal narcotics. Anaesthesia 1980: 35: 1080- 1083.

48. GIynn C > J , Mather L E, Cousins M J, Wilson P R, Graham J R. Spinal narrotics and respiratory depression. Lancet 1979: i: 35fj-357.

49. Riggs I) S. 'I'he mathematical approach to physiological proh- Ienis. Cambridge: M.I.T. Press, 1969: 173-1 79.

50. Payne K, Foley K M, Inturrisi C E. CSF pharmacokinetics of opiates in a sheep model. In: Foley K M, Inturrisi C E, eds.

.V~/uur~su~g 1975: 42: 674-678.

8 14-8 1 7.

iiW.\ //lt'iZ(JkJgy 1 983 : 58: 25 7-262.

u,<>' 1981: 55: 714-715.

Ills. KUdifJlfqp 1979: 130: 681-686.

Advances in pain research and therapy. New York: Raven Press,

51. Lee V C, Burns R S, Dubois M, Cohen M R. Clearance from cerebrospinal fluid of intrathecally administered p-endorphin in monkeys. Anesth Analg 1984: 63: 511-514.

52. Lin S H, Tremper K K. Clearance from cerebrospinal fluid of intrathecally administered p-endorphin in monkrys. Anesth Analg

53. Yaksh T L, Gross K E, Li C H . Studies of the intratheral eflect of beta-endorphin. Brain Res 1982: 241: 261-269.

54. Hosohuchi Y, Li C H. The analgesic activity of human p- endorphin in man. Comm Psychopharm 1978: 2: 33-37.

55. Oyama T, Jin T, Yamaya R. Profound analgesic efferts of p- endorphin in man. Lancet 1980: i: 122-124.

56. Foley K, Kourides I A, Inturrisi C E, Kaiko K F, Zaroulis C G, Posncr J B, Houde R W, Li C H. p-endorphin: analgesic and hormonal effects in humans. Proc Natl Acad Sci USA 1979: 76:

57. Heisey S R, Held D, Pappenheimer J R. Bulk flow and diffusion in the cerebrospinal fluid of the goat. A m 3 P h y d 1962: 203:

58. Gorsteein C, Snyder S H. Enkephalinases. Proc K Sac Lond 1980:

59. Austen B M, Smyth D G, Snell C R. Gamma-endorphin, alpha- endorphin, and meth-enkephalin are formed extracellularly from lipotropin C-fragment. .Nature 1977: 269: 619-621.

60. Onofrio B M, Yaksh T L, Arnold P G. Continuous low-dosr intratheeal morphine administration in the treatment of chronic pain of malignant origin. Myo Clin Proc 1981: 56: 516-520.

61. Coombs D W, Saunders R L, Gaylor M S, Block A R , Colton T, Harbaugh R, Pageau M G, Mroz W. Relief of'continuous chronic pain by intraspinal narcotics infusion via an implanted reservoir. 3AMA 1983: 250: 2336-2339.

62. Yaksh T L. In vim studies on spinal opiate receptor systems mediating anti-noeiception. I M u and delta receptor profiles in the primate. 3 Pharmacol Exp The7 1983: 226: 301-316.

63. Coomhs D W, Saunders R L, Lachanre D, Savage S, Ragnarsson T S, Jensen L E. Intrathecal morphine toleranre: use of intrathrcal clonidine, DADLE, and intraventricular morphine. AnestheJi-

64. Batson 0 V. The vertebral vein system. A m 3 Roenlgenol 1957:

65. Chauvin M, Samii K, Schermann J M, Sandouk l', Bourdon R, Viars P. Plasma pharmacokinetics of morphine after i m . , extradural and intrathecal administration. Br 3 Anaeslh 1982:

66. Kao L I , Crill W E. Penicillin-induced segmental myoclonus. I . Motor responses and intraeellular recording from rnotoneurons. Arch Neurol 1972: 26: 156-161.

67. Lothman E W, Somjen G G. Motor and electrical signs of epileptiform activity induced by penicillin in the spinal rord of decapitate cats. Electroencephalogr Clin Neurophysiol 1976: 41:

68. Duggan A W, Hall J G, Headley P M. Suppression of transmission of nociceptive impulses by morphine: selective effects of morphine administered in the region ofsuhstantia gelatinosa. Hr 3 Pharmacol 1977: 61: 65-76.

69. Bullingham R E S, McQuay H J , Moore R A. Extrddurdl and intrathrral narcotics. In: Atkinson R S, Longton Hcwcr C L, eds. Recent advances in anaesthesia arid analgesia. Edinburgh: Churchill Livingstonc, 1982: 141 156.

70. Yeung J C, Rudy T A. Multiplicative intrraction between narcotic agonisms expressed at spinal and supraspinal sites orantino- riceptive action as revealed by concurrent intrathecal and intra- cerchrovcntricular injections of morphine. 3 Pharmacol Ex!> Ther

1986: 385-390.

1985: 64: 180-181.

537775381,

775-781.

B210: 123-132.

0 1 0 ~ 1985: 62: 358-363.

78: 195-212

54: 843-846.

237-25 2.

1980: 61: 65-76.

46 R . P

71. Crawford J S. Site of action of intraheral morphine. H r Med .7 1980: 281: 680.

72. Crawford J S. Site of action of intrathecal morphine. Br Med 3 1980: 281: 1444.

73. Rciz S, Westberg iM. Sidc-rff of epidural morphine. Lancet 1980: i: 203-204.

74. Bromagr P R. Dangers and complications of intrathecal and epidural opiates. In: Yaksh ‘I L, Muller H , eds. Spinal opiate analgcsia: experirncntal and clinical studies. Berlin: Spinger- Verlag, 1982: 18-23.

75. Gustafson L L, Schildt B, Jacohsen. Adverse effects ofextradural and intrathecal opiates: report ofa nationwide survey in Sweden. Br .7 Anaesth 1982: 54: 479--485.

76. Glass P S A. Respiratory depression following only 0.4 mg of intrathecal morphine. Anesthesiology 1984: 60: 256-257.

77 . Stanley T H . Intrathrcal opiates, nt tool to be used with caution. Anesthesiolyq 1980: 53: 53

78. Baraka A. Rostral spread of intrathecal morphine in man. ME.7 AnaeJth 1982: 6: 178-1 79.

79. Liolios A, Aridrrsen F H. Selective spinal analgesia. Lancet 1979: ii: 357.

80. Sammi K , Frrct J , Harari A, Viars P. Srlrrtivr spinal analgesia. Lancet 1979: i: 1142.

81. Grcrnberg H S, ’Iaren J, Ensmingcr W, Doan K. Benefit from and tolerance to continuous intratheral infusion of morphine for intractable cancer pain. 3 N e u r o w g 1982: 57: 360-364.

82. ‘Iorda ’I’ A, Pybus D A. Comparison of four narcotic analgesics for tfxtradural analgesia. Rr ,7 Anaesth 1982: 54: 291-294.

83. Andrrsrn E F. Epidural and intratheral narcotics for pain relief. SD .7 Med 1984: 37: 7-12.

84. Berhy 13, Maclntosh K C, Bailey M , Welch D B. Postoperative analgesia f i r caesarean section using epidural methadone. Anaes-

85. Welrh D B, Hrynaszkiewicz A. Postoperative analgesia using rpidural methadone. Administration by the lumbar route for thoracir pain relief. Anaesthesia 1981: 36: 1051-1054.

86. Gallon A M. Epidural analgesia for thoracotomy patients. Physio- therapy 1982: 68: 193.

theria 1984: 39: 61-63.

‘AYNE

87. Welchew E A, Thronton J A. Continuous thoracic epidural fentanyl. Anaesthesia 1982: 37: 309-316.

88. Bromage P R, Camporesi E M, Durant 1’ A C, Niclsen C: H. Rostral spread of epidural morphine. Anesthesiology 1982: 56:

89. Tamsen A, Sakurada T, Wahlstrom A, ’Ierenius L, Hartvig 1’. Postoperative demand for analgesics in relation to individual levels of endorphins and substance I’ in cerebrospinal fluid. f’nirr

90. Brownridge P R , Wrobel J , Watt-Smith J . Rcspiratory tlc- pression following accidental subarachnoid pethidinr. ilnnvrtlr Intensiue Care 1983: 11: 237-240.

91. Tung A S, Yaksh T L. T h e antinociceptive effects of cpidur,il opiates in the cat: studies on the pharmacology arid thc r l i i ~ t ~ of lipophilicity in spinal analgesia. Pain 1982: 12: 343--356.

92. Moulin D, Max M, Kaiko R , Inturrisi C E, Maggard J , t‘c11t.y K M. T h e analgesic efficacy of intrathecal (1’1‘) D-ala-D-lru enkephalin (DADL) in cancer patients with chronic pain. Pain (Suppl) 1984: 2: S343.

93. Coyle D E, Parah P V, Streng W H, Denson U D, Ritsclicl W A. Is hydromorphone more lipid snluble than morphiirr.’ Anesthesiology 1984: 61: A240.

94. Herz H, Teschmacher H J, Hess R . Structure-activity rclatioii- ship of morphine analgesics. J Med Chem 1970: 13: 801-80.5.

95. Kaufmann J J, Semo N M, Koski W S. Microelectrodr titration measurements of the pKa’s and partition and drug distributioii roefficients of narcotics and narcotic antagonists and thcir pH and temperature dependence. 3 Med Chem 1975: 18: 647-655.

96. Fredrickson R C A. Endogenous opioids and related drrivativcs. In: Kuhar M J, Pasternak G W, eds. Analgesics: nrurochemic;il, behavioral and clinical perspectives. New York: Raven Press,

431-436.

1982: 13: 171-173.

1984: 9-68.

Address: Richard Payne, M.D. Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, New York 10021, USA Tel: (212) 794-6594

Date post:	30-Sep-2016
Category:	Documents
Upload:	richard-payne
View:	215 times
Download:	1 times

CSF distribution of opioids in animals and man

Documents