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Long-term observation of the relation between pain intensity and serum carbamazepine concentration in elderly patients with trigeminal neuralgia
J Oral Maxillolac Surg 51:1336·1344.1993
Long-Term Observation of the Relation Between Pain Intensity and Serum Carbamazepine Concentration in Elderly Patients With Trigeminal Neuralgia MASAHIRO UMINO, DDS, PHD,* TSUNETO OHWATARI, DDS, PHD,t KAZUHIRO SHIMOYAMA, DDS, PHD,+ AND MASANORI NAGAO, DDS, PHD§ The relation between changes in pain intensity and serum carbamazepine (CBZ) concentration was studied in five elderly patients with trigeminal neuralgia. Measurement of pain intensity and serum CBZ concentration, and blood studies, were performed approximately every 2 or 3 months after initiation of CBZ therapy. Fluctuations in pain intensity were observed in four patients. In these patients, even when the serum CBZ concentration was maintained within a relatively high range, there were periods in which pain intensity increased. On the other hand, there were periods in which pain was relatively well controlled even though the CBZ concentration was relatively low. There were considerable interindividual differences in response to CBZ. The fluctuations in pain showed that the CBZ response curve varies from ' period to period even within an individual. It was concluded that it is essential to observe spontaneous variations in pain intensity and monitor serum CBZ during long-term administration.
disorders, and hematologic abnormalities.S" Side effects tend to develop particularly in elderly patients because of hypoalbuminemia, hypoproteinemia, and changes in pharmacodynamics or pharmacokinetics. These side effects increase as the dosage is increased. Accordingly, the initial dose is kept small to prevent side effects, and then gradually increased until pain relief is obtained," However, even when such a method ofadministration is used, it is occasionally necessary to restrict the dose of CBZ before obtaining the desired effect because of the occurrence of side effects. We experienced several cases in which we were compelled to restrict CBZ dosage when severe side effects developed after administration to elderly patients with trigeminal neuralgia. Although complete pain relief was not always obtained in response to CBZ administration, the relative pain relief still made it possible for there not to be interefercnce with activities of daily living. In such patients, the therapeutic effects of CBZ should be monitored, paying attention to the development of side effects. At present, however, there have been few reports of long-term observations of the therapeutic effects of CBZ. 8 We investigated the relation between changes in pain intensity and serum CBZ concentration in the situation in which it was necessary to restrict the dose of CBZ
Carbamazepine (CBZ) is an iminostilbene derivative that has anticonvulsant and anti neuralgic effects. Thus, it has been used in the treatment of epilepsy. Since CBZ was first introduced for use in trigeminal neuralgia by Blom in 1962,1 it has become the drug of choice in the management ofthis condition.i-' The effect ofCBZ is rapid; 69% of patients experience pain relief within 24 hours and 93% by 48 hours.' Nevertheless, CBZ has side effects, and they are most prominent at the time of initiation of therapy. Sillanpa" reviewed the literature on the side effects of CBZ and reported that the rate was 21%. The most common symptoms are dizziness, drowsiness, nausea, skin reactions, generalized weakness, appetite loss, ataxia, gastrointestinal Received from the Department of Geriatric Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo, Japan. • Associate Professor. t Research Associate. Lecturer. § Professor and Chairman. Address correspondence and reprint requests to Dr Umino: Departrnent of Geriatric Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, 1-5-45, Yushima, l-Chorne, Bunkyo-ku, Tokyo. Japan.
*
© 1993 American Association of Oral and Maxillofacial Surgeons 0278-2391/93/5112-0010$3.00/0
1338
1339
UMINO ET AL and attempted to characterize trigeminal neuralgia in elderly patients during CBZ administration.
Methods PATIENTS Five elderly patients with trigeminal neuralgia, 66 to 77 years old, gave their informed consent and were assessed. No patients had a history of any other neurologic diseases. No evidence of organic disturbances of the face, maxillary sinus, mandible, or temporomandibular joint were found on radiographic examination. The diagnosis of trigeminal neuralgia was made on the basis of the history and diagnostic criteria for trigeminal neuralgia." The patients' characteristics are shown in Table I. All patients refused neurosurgical treatment, neurectomy, or alcohol nerve block, preferring CBZ below the dose inducing side effects. They agreed to pain relief by local anesthesia when pain increased. SYMPTOMS BEFORE TREATMENT AND DETERMINATION OF CBZ DOSAGE
Case 1 The patient had been treated with 800 mg ofCBZ per day for I month at another hospital before coming to our hospital, but the drug was suspended because of severe side effects. Table 1.
Before treatment, extremely severe pain was provoked by talking, eating, touch, and vibration. The frequency of pain attacks reached 15 to 20 times a day. Daily life was extremely compromised by the paroxysmal pain. After treating the patient with 200 mg of CBZ twice a day for I week, she was given 200 mg of CBZ three times a day for an additional week. Severe pain attacks were relieved, but pain relief was incomplete. Therefore, 200 mg of CBZ was given four times a day, but severe dizziness, difficulty in walking, and ataxia developed. Two hundred milligrams of CBZ, three times daily, or less occasionally, was selected as the daily dose.
Case 2 Before treatment, the frequency of pain attacks was 15 times a day, and paroxysmal pain was induced by talking, eating, and touch. This led to impaired activities of daily living, such as difficulty in conversation and food ingestion. When 200 mg ofCBZ was administered two times a day for 2 weeks, the severe attacks were reduced, but pain was not relieved completely. Accordingly, 200 mg ofCBZ was given three times a day for a week, but drowsiness, dizziness, generalized weakness, and nausea resulting in difficulty in eating developed. Therefore, 200 mg ofCBZ (occasionally less), two times daily was chosen as the therapeutic regimen.
Case 3 The frequency of pain attacks in this patient was 14 or 15 a day before therapy. Extremely severe pain was induced by talking, eating, touch, and tongue movements. In daily life, conversation and food ingestion were difficult because of the paroxysmal pain. The patient was initially treated with 100 rng of CBZ twice a day for 2 weeks and then 200 mg of CBZ
Clinical Characteristics of the Five Patients With Trigeminal Neuralgia
Sex/Age (yr)
Weight (kg)
Duration of Trigeminal Neuralgia Prior to Diagnosis (mo)
F/66
56
18
R·I1
Right upper lip
2
MI73
65
4
R-llI
3
F/75
45
3
L-llI
4
Ff77
43
6
R-lll
Gingiva around the right mandibular molar teeth Gingiva around the left mandibular molar region Right margin on tongue
5
F/7l
46
3
R-I1
Right upper lip
Talking, tongue
Patient No.
Location of Trigeminal Neuralgia
Trigger Zone
Treatment Prior to CBZ
Provoking Factor of Pain
Frequency of Pain Attack
Talking. eating, touch, vibration Talking, eating. touch
15 - 20 times/day (great) More than 15 times/day (great)
CBZ
Angina pectoris
Dental treatment, local anesthesia
Diabetes mellitus, hypertension
Talking, eating, touch, tongue movement
14 or 15 times/day (great)
None
None
Nitroglycerin at anginal attack Hypoglycemic agent (drug name unknown), propranolol None
Talking, eating, tongue
15 - 20 times/day (great) More than to times/day (frequent)
None
None
None
Acupuncture
Hypertension
Nifedipine
movement
movement,
Complicating Diseases
opening mouth
Abbreviations: R, right; L, left; II, maxillary division trigeminal nerve; III, mandibular division trigeminal nerve.
Medication
CARBAMAZEPINE AND TRIGEMINAL NEURALGIA
1340 additionally twice a day for I week. Occasional pain attacks developed during treatment. Consequently, 200 mg ofCBZ was given three times a day. After taking CBZ at this dose, the patient developed difficulty in walking, dizziness, and generalized weakness. Accordingly, 200 mg or less of CBZ twice daily was prescribed as the daily dose.
Case 4 The frequency of pain attacks reached 15 to 20 times a day in this patient. Provoking factors were talking, eating, and tongue movements. It was difficult for the patient to consume anything except canned liquid meals. An initial dose of 100 mgofCBZ was given twiceaday for 2 weeks. Although the pain attacks diminished, the patient complained of dizziness, nausea, appetite loss, gastrointestinal disorders, and difficulty in walking. CBZ 50 mg twice or occasionally three times a day was chosen as the dose.
Case 5 The frequency of pain attacks was approximately 10 times a day in this patient. Paroxysmal pain was provoked by tongue movements, opening the mouth, and talking. CBZ, 100 mg, was initially given once a day for a week. Since complete pain reliefwas not obtained, 100 rng ofCBZ was given twice a day. The patient developed difficulty in walking, dizziness, and generalized weakness. Therefore, 50 mg of CBZ twice a day was selected as the daily dose. CBZ doses were occasionally adjusted further when side effects or hematologic abnormalities developed in individual cases.
MEASUREMENT OF PAIN INTENSITY A visual analogue scale (VAS) consisting of a 100mm horizontal straight line, the left end representing "no pain" and the right end the "worst pain," was used to determine pain intensity before therapy. Patients were then requested at the time of blood sampling to indicate on the VAS the worst pain intensity experienced during the preceding week, and this was compared with the worst pain reported before therapy. RECORDING OF PAIN ATTACKS At the time of blood sampling, the patients were instructed to indicate the frequency of average daily pain attacks for the preceding weeks as great (over 15 til11~s a day), frequent (10 to 14 times a day), moderate (five to nine times a day), few (one to four times a day), or none (zero times a day). RECORDING OF PROVOKING FACTORS AND SIDE EFFECTS Provoking factors and side effects were investigated at the time of interview every 2 weeks. RECORDING OFTHE CBZ DOSAGE
MEASUREMENT OF SERUM CBZ CONCENTRATIONS Four milliliters of venous blood were collected between IO AM and 12 AM. These samples were immediately centrifuged for 20 minutes at 4°C, and the sera were separated. Total serum CBZ concentration was measured by the fluorescence polarization immunoassay method 10 using a TDX Drug Assay-Carbamazepine Kit (Abbott Laboratories Diagnostic Division, North Chicago, IL). The coefficient value of this kit was less than 3.9%, and sensitivity was 0.5 pg/mL. The average recovery was IOI% ± 1.3%, and the rate of cross-reaction to CBZ-IO,II-epoxide (CBZ-E) was 13.2%. A TDX Fluorescence Polarization Analyzer (Abbott Laboratories Diagnostic Division) was used as the measuring instrument. Patients all took CBZ upon awakening on the day of blood sampling. BLOOD EXAMINATION Measurement of red blood cells, white blood cells, hemoglobin, hematocrit, and a differential white cell count were performed using an automated hematology analyzer (Coulter Counter T660, Coulter Techtronics, Inc, Hialeah, FL). Blood chemistry studies were performed using an automatic analyzer (Hitachi model 7150, Japan). These examinations were performed at the same time serum CBZ concentrations were measured.
Patients were requested to record daily CBZ intake at home. The daily CBZ doses for the preceding week were recorded at the time of blood sampling. VAS recording, measurement of serum CBZ concentration, and blood studies were performed approximately every 2 or 3 months after initiation of CBZ therapy.
Results
Case 1 Fluctuations in pain were observed after CBZ therapy. Severe pain persisted after 2 months, despite high serum CBZ concentrations. After 8 months of using CBZ, complete pain relief was obtained. After 12 months of using CBZ, pain intensity and the frequency of pain attacks again increased. The effects of CBZ were inadequate despite the high serum concentrations at 2 and 12 months. At these times, local anesthesia with 2% lidocaine was administered in the pain-provoking area. After 12 months, complete pain relief continued for another 5 months. After that, the patient consented to neurosurgical treatment and underwent a microvascular decompression procedure. Side effectsand hematologic abnormalities were transient (Table 2).
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UMINO ET AL
Table 2.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 1 Months After CBZ Treatment 4
CBZ dose (rng/d) Serum CBZ concentration (l'g/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain Side effects Abnormal hematologic findings Other treatment
12
6
16
14
19
600 10.9
400 8.1
400 6.9
300 5.8
600 13.1
500 9.6
400 6.4
70
8
8
0
71
0
0
16
Frequent
Few
Few
None
Frequent
None
None
Few
Talking, eating, touch Dizziness
Eating
Eating. washing face
Talking. eating. touch
400 9.4
Talking. eating
Leukopeniadecreased serum calcium
Leukopenia
Local anesthesia
Local . anesthesia
Case Z
with 2% lidocaine was given in the provoking area a few times, the patient was subsequently unable to come for further injections because of hospitalization for treatment ofa gallstone. During this period the patient continued to take 400 mg of CBZ. After 15 months, pain intensity and attacks gradually decreased despite the low serum CBZ concentrations. Side effects were transient; there was transient leukopenia, elevation of 'Y-guanosine triphosphate, glutamine-oxaloacetic transaminase, and glutamic-pyruvic transaminase among the hematologic findings (Table 4).
Pain intensity and attacks decreased in response to CBZ, compared with pretreatment levels. However, although serum CBZ concentrations remained stable at between 8.0 and 10.2 pg/mL, pain intensity fluctuated after 4 and 8 months. During this period there were instances of resistance to CBZ, and 2% lidocaine was administered in the provoking area for pain relief. There were transient side effects and hematologic abnormalities (Table 3).
Case 3 Case 4
Pain intensity and attacks were relatively well controlled after 2 months of CBZ, despite the low serum concentrations. After 4 months, pain intensity and attacks increased and inadequate analgesia persisted for several months despite relatively high serum concentrations. Although during this time local anesthesia
Table 3.
Despite the stable CBZ serum concentrations, relatively weak fluctuations in pain intensity were recognized. Pain intensity and attacks gradually decreased, becoming "slight" after to months ofCBZ. However, pain again became intense 13 months after CBZ had
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 2 Months After CBZ Treatment 2
CBZ dose (mg/d) Serum CBZ concentration (Jlg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain Side effects Abnormal hematologic findings Other treatment
6
4
II
300 8.0
400 9.6
400
10.2
400 9.3
10
45
20
40
16
Few Touch, brushing Drows iness
Moderate Talking, eating, shaving
Few Talking, brushing
Moderate Talking,
Fcw Eating
Increased eosinophils Local anesthesia
eating Dizziness
400 9.2
1342 Table 4.
CARBAMAZEPINE AND TRIGEMINAL NEURALGIA
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 3 Months After CBZ Treatment 15
4
CBZ dose (mg/d) Serum CBZ concentration (pg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain
17
400
200
400 7.4
300 7.3
400
2.8
9.2
400 1.5
9 Few Talking, eating
51
53
48
33
17
Moderate Swallowing, talking, eating
Frequent Talking, eating, touch
Moderate Talking. eating, touch
Moderate Talking, eating
Few Eating
Side effects
2.8
Dizziness
Abnormal hematologic findings
Decreased serum calcium
Other treatment
Local ane~thesia
Leukopenia, elevated "Y·G T P, GPT, and GOT
Abbreviations: GTP, guanosine triphosphate; GPT, glutamic-pyruvic transaminase; GOT, glutarnic-oxaloacetic transaminase.
been started, although during this period stable but low serum CBZ concentrations were maintained. Side effects and hematologic abnormalities were transient (Table 5).
Case 5 Pain intensity and attacks gradually decreased after CBZ therapy and, by 4 months, complete pain relief was obtained and the patient no longer required medication. Transient, severe leukopenia developed, but there was subsequently a return to normal levels (Table 6). Discussion
Several methods of pain assessment have been used to evaluate clinical pain and determine the effect of Table S.
analgesic drugs, although the problems in measurement are also well recognized. II The pain score and Verbal Rating Scales(VRS) frequently have been used to assess pain in trigeminal neuralgia and the therapeutic effects ofCBZ,12,'3 because the pain score and VRS are more appropriate than the VAS to assess pain magnitude in cases of paroxysmal and refractory pain such as in trigeminal neuralgia. These tests evaluate three elements: intensity, frequency, and duration, whereas VAS is a simple, quantitative, and continuous scale, and is appropriate to assess pain intensity.I':" Therefore, if the focus of pain assessment is only pain intensity, it is possible to use the VAS to assess pain in trigeminal neuralgia. 15 In addition, it was too difficult for our elderly patients to maintain a long-term pain score diary. For these reasons, VAS was used to assess pain in the present study. At the same time, the frequency of pain attacks also was recorded with a stepwise scale.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 4 Months After CBZ Treatment
CBZ dose (mg/d) Serum caz concentration (pg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain
100
150
100
100
100
3.7
4.9
3.8
3.0
3.4
30
16
Moderate Swallowing, eating, cough
Few Talking, rinsing, yawning
18 Moderate Talking, eating
7 Few Eating
6 Few Washing face
Side effects Abnormal hematologic findings
II
9
4
Leukopenia
Leukopenia increased, segmented
Gastrointestinal disorders Leukopenia decreased, lymphocytes
13
100 3.2 36 Moderate Washing face, jaw movement
1343
UMINO ET AL
Table 6.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 5 Months After CBZ Tre atment 10
4
CI3Z dose (mg/d) Serum CBZ concentration
100 1.0
0 0.5
0 0
0 0
44
16
Mod erate Touch, jaw movement
Few Touch
0 None
0 None
0 Non e
100 1.6
(~g/mL)
Pain int ensity (mm) Frequency of pain attack Provo king factors of pain Side effects Abnormal hematologic findings
The therapeutic effects ofCBZ were correlated with the serum CBZ concentration. Since there is a linear relationship between the dose and serum concentration of CBZ,12 the higher the serum CBZ concentration, the better the expected therapeutic effects. Tomson et al 12 reported that the optimal effect was seen at CBZ levels between 5.7 and 10.1 IlgfmL. In this study serum CBZ concentrations in patients 1,2, and 3 (except for one time period) were within the effective range reported by Tomson et al." However, in these cases, even when the serum CBZ concentration was maintained within a relatively high range, there were periods in which pain intensity increased . On the other hand, there were periods in which pain was relatively well controlled even though the serum CBZ concentration was relatively low. Such fluctuations in pain intensity show that the CBZ response curve varies from period to period even within an individual. Unstable CBZ response curves are due to instability and spontaneous variations in pain in trigeminal neuralgia . The pain magnitude in trigeminal neuralgia is determined by a balance between spontaneous variations in pain and serum CBZ concentrations while on CBZ therapy. When the spontaneous variation of pain is in the active period, response to CBZ decreases. Taylor and Brauer" also have indicated that resistance to CBZ is induced by longterm administration ofCBZ. On the other hand, when the spontaneous variation in pain enters an inactive period, even low-serum CBZ concentrations are effective. Autoinduction by CBZ during long-term administration is another cause of fluctuations in pain. Autoinduction of liver microsomal enzymes during longterm .drug administration leads to shortening of the half-life of CBZ, reduced serum concentrations, and lessened therapeutic effects.":" In the present study, only one case (no. 3) showed a decrease in serum CBZ concentration (1.5 and 2.8 Ilg/mL on a 400-mg daily dose of CBZ for 15 and 17 months, respectively) in which the discrepancy between dose and serum concentration might have been caused by autoinduction.
Leukopenia
The primary metabolite of CBZ, CBZ-E, also may be a factor influencing therapeutic effect.18 CBZ-E itself has potent therapeutic effectson trigeminal neuralgia.19 CBZ-E levels are correlated with the doses and serum concentrations of CBZ.20 Bertilsson and Tomson" have shown that the serum CBZ-E concentration is between 10% and 50% of the serum CBZ concentration. Monaco et al,22 on the other hand, postulated that the plasma CBZ-E concentration fluctuated markedly, independent ofCBZ level, during long-term administration. Although we did not measure serum CBZ-E concentrations in the present study, enhanced CBZ-E formation may have occurred during the longterm administration in our cases. It is likely that CBZE formation may have been a cause of pain fluctuation. In our cases there were considerable interindividual differences in response to CBZ. In case 4, pain was relatively well controlled without disturbance of the patient's daily life despite CBZ concentrations below the most effective levels reported by Tomson et al." In case 5, the patient also responded well to extremely low serum CBZ concentrations, with pain eventually disappearing spontaneously. In cases I, 2, and 3, on the other hand, higher serum CBZ concentrations were required than in cases 4 and 5 to obtain well-controlled pain relief. The interindividual differences in response to CBZ may be due to differences in the severity of trigeminal neuralgia, pharmacokinetics, and methods of pain assessment. However, it was difficult to determine the main cause of the interindividual differences in response to CBZ. In any case, interindividual differences in response to CBZ appear to be frequent in elderly patients. As pain intensity fluctuates in trigeminal neuralgia, satisfactory pain relief can be obtained temporarily even with CBZ doses restricted because of side effects. Therefore, it is essential to observe spontaneous variations in pain intensity and the therapeutic effect of CBZ during long-term administration. It is recommended that serum CBZ and CBZ-E concentrations be monitored while recording pain intensity periodically in elderly patients. If such monitoring is per-
1344
DISCUSSION
formed, it is not only possible to know the response to CBZ, the fluctuations in the rhythm of the pain, and the characteristics of the pain, but also to avoid an overdose of CBZ, to make adjustments to the CBZ dose, and to decide on indications for neurosurgical procedures or alcohol nerve block. Acknowledgment The authors wish to acknowledge Dr Hiroyasu Akatuka, Division of Biochemistry, Mitsubishi Yuka Bio-Clinical Laboratories, Inc (Tokyo, Japan) for cooperation in measurement of the serum CBZ concentrations.
References I. B10mS: Trigeminal neuralgia: Its treatment with a new anticonvulsant drug (G32883). Lancet 1:839, 1962 2. B10m S: Tic douloureux treated with new anticonvulsant, Experiences with G32883. Arch Neurol 9:285, 1963 3. Rasmusse P, Riishede J: Facial pain treated with carbamazepin (Tegretol). Acta Neural Scand 46:385, 1970 4. Sillanpa M: Carbamazepine pharmacology and clinical use. Acta Neurol Scand 88:115, 1981 (SuppI64) 5. Killian JM, Fromm GH: Carbamazepine in the treatment of neuralgia, Use and side effects. Arch Neural 19:129, 1968 6. Zakrewska JM: Medical management of trigeminal neuralgia. Br Dent J 168:399, 1990 7. Zakrewska JM, Patsalos PN: Drugs used in the management of trigeminal neuralgia. Oral Surg Oral Med Oral PathoI74:439, 1992 8. Taylor JC, Brauer S: long-term treatment of trigeminal neuralgia with carbamazepine. Post Med J 57:16, 1981
9. Bell WE: Orofacial Pains, Classification, Diagnosis, Management (ed 4). Chicago, Il., Year Book, 1989, p 377 10. McGregor AR, Crookall-Greening JO, Landon J, et al: Polarisation fluoraiminunoassay of'phenytoin. Clin Chim Acta 83: 161,1978 I I. Chapman CR, Casey Kl., Dubner R, et al: Pain measurement: An overview. Pain 22:1, 1985 12. Tomson T, Tybring G, Bertilson L, et al: Carbamazepine therapy in trigeminal neuralgia, Clinical effects in relation to plasma concentration. Arch Neural 37:699, 1980 13. Fargo F: Trigeminal neuralgia: Its treatment with two new carbamazepine analogues. Eur Neural 26:73, 1987 14. Kremer E, Atkinson JH, Ignelzi RJ: Measurement ofpain: Patient preference does not confound pain measurement. Pain 10: 241,1981 15. Sharav Y, Benoliel R, Schnarch A, et al: Idiopathic trigeminal pain associated with gustatory stimuli. Pain 44:171, 1991 16. Eichelbaum M, Ekbom K, Bertilsson L, et al: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin PharmacoI8:337, 1975 17. Morsell Pl., Frigerio A: Metabolism and pharmacokinetics of carbamazepine. Drug Metab Rev 4:97, 1975 18. Bertilsson L: Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet 3:128, 1978 19. Tomson T, Bertilsson L: Potent therapeutic effect ofcarbamazepine-Hl.l l-epoxide in trigeminal neuralgia. Arch Neural 41: 598, 1984 20. Elyas AA, Patsalos PN, Agbato OA, et al: Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-Ht.l l-epoxide in serum of children with epilepsy. Ther Drug Monit 8:288, 1986 21. Bertilsson L, Tomson T: Clinical pharmacokinetics and pharmacological effects of carbarnazepine and carbarnazeplneIO,II-epoxide. C1in Pharmacokinet 11:177, 1986 22. Monaco F, Riccio A, Benna P, et al: Further observations on carbamazepine plasma levels in epileptic patients. Neurology 26:936, 1976
J Oral Maxillofac Surg 51 :1344-1345. 1993
Discussion Long-Term Observation of the Relation Between Pain Intensity and Serum Carbamazepine Concentration in Elderly Patients With Trigeminal Neuralgia John R. Zuniga, DMD, MS, PHD UniversityofNorth Carolina School ofDentistry, Chapel Hill, NC
Carbamazepine (Tegretol; Basel Pharmaceuticals, Summit, NJ) is the preferred drug for the initial and long-term management of trigeminal neuralgia (TN). Its mechanism of action is unknown; however, within the spinal trigeminal nucleus it increases seizure threshold, inhibits the release of excitatory neurotransmitters, and inhibits synaptic transmission. The anti neuralgic effect of carbamazepine is rapid, but a dose of 200 to 1600 mg daily is often required to gain good pain control. Side effects (21%)are dose-dependant and transient, occurring mainly during initial therapy, frequently in the elderly, and after a rapid increase in dose. Thus, most clinicians titrate the drug slowly to the occurrence of pain relief or side effects by changing the dose, 200 mg at a time, every 2 to 3 days. More than half of the patients with TN (56%) respond to long-term carbamazepine therapy. Serious hematologic and hepatotoxic side effects may occur during long-term therapy and necessitate monthly screening.
The goal of this study was to examine the relationship between the subjective pain intensity of TN and serum carbamazepine (CBZ) concentration in five patients over a 2to 19-month treatment period. The hypothesis was that TN pain relief is related (linearly) to serum CBZ concentration and that monitoring serum CBZ is a valuable tool in the clinical management of TN. However, there are no statistical data presented to support this hypothesis. To show these facts, the CBZ dose (rng/d), serum CBZ concentration (j.lg/mL), pain intensity (millimeters), and pain frequency (converted from descriptions provided in the text) data from Tables 2 through 6 were subjected to parametric and nonparametric statistical analysis. Multivariate linear regression was used to describe the relation between serum CBZ concentration and pain intensity and frequency, and Spearman correlation analysis was performed to evaluate the association between dose, pain frequency and intensity, and the regression coefficient ofserum CBZ concentrations. The level ofconfidence was set at 0.05. The results are presented in Table I, and they show that there was no significant relationship between serum CBZ concentration and pain intensity (P = .385, r = .23) or pain frequency (P = .748, r = .12). There was a significant relationship, however, between CBZ dose and serum CBZ concentration (P = .00 I, r = .8l). These findings can be explained by review ofthe literature. It is true that Tomson et al' demonstrated a positive rela-
Long-Term Observation of the Relation Between Pain Intensity and Serum Carbamazepine Concentration in Elderly Patients With Trigeminal Neuralgia MASAHIRO UMINO, DDS, PHD,* TSUNETO OHWATARI, DDS, PHD,t KAZUHIRO SHIMOYAMA, DDS, PHD,+ AND MASANORI NAGAO, DDS, PHD§ The relation between changes in pain intensity and serum carbamazepine (CBZ) concentration was studied in five elderly patients with trigeminal neuralgia. Measurement of pain intensity and serum CBZ concentration, and blood studies, were performed approximately every 2 or 3 months after initiation of CBZ therapy. Fluctuations in pain intensity were observed in four patients. In these patients, even when the serum CBZ concentration was maintained within a relatively high range, there were periods in which pain intensity increased. On the other hand, there were periods in which pain was relatively well controlled even though the CBZ concentration was relatively low. There were considerable interindividual differences in response to CBZ. The fluctuations in pain showed that the CBZ response curve varies from ' period to period even within an individual. It was concluded that it is essential to observe spontaneous variations in pain intensity and monitor serum CBZ during long-term administration.
disorders, and hematologic abnormalities.S" Side effects tend to develop particularly in elderly patients because of hypoalbuminemia, hypoproteinemia, and changes in pharmacodynamics or pharmacokinetics. These side effects increase as the dosage is increased. Accordingly, the initial dose is kept small to prevent side effects, and then gradually increased until pain relief is obtained," However, even when such a method ofadministration is used, it is occasionally necessary to restrict the dose of CBZ before obtaining the desired effect because of the occurrence of side effects. We experienced several cases in which we were compelled to restrict CBZ dosage when severe side effects developed after administration to elderly patients with trigeminal neuralgia. Although complete pain relief was not always obtained in response to CBZ administration, the relative pain relief still made it possible for there not to be interefercnce with activities of daily living. In such patients, the therapeutic effects of CBZ should be monitored, paying attention to the development of side effects. At present, however, there have been few reports of long-term observations of the therapeutic effects of CBZ. 8 We investigated the relation between changes in pain intensity and serum CBZ concentration in the situation in which it was necessary to restrict the dose of CBZ
Carbamazepine (CBZ) is an iminostilbene derivative that has anticonvulsant and anti neuralgic effects. Thus, it has been used in the treatment of epilepsy. Since CBZ was first introduced for use in trigeminal neuralgia by Blom in 1962,1 it has become the drug of choice in the management ofthis condition.i-' The effect ofCBZ is rapid; 69% of patients experience pain relief within 24 hours and 93% by 48 hours.' Nevertheless, CBZ has side effects, and they are most prominent at the time of initiation of therapy. Sillanpa" reviewed the literature on the side effects of CBZ and reported that the rate was 21%. The most common symptoms are dizziness, drowsiness, nausea, skin reactions, generalized weakness, appetite loss, ataxia, gastrointestinal Received from the Department of Geriatric Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo, Japan. • Associate Professor. t Research Associate. Lecturer. § Professor and Chairman. Address correspondence and reprint requests to Dr Umino: Departrnent of Geriatric Dentistry, Faculty of Dentistry, Tokyo Medical and Dental University, 1-5-45, Yushima, l-Chorne, Bunkyo-ku, Tokyo. Japan.
*
© 1993 American Association of Oral and Maxillofacial Surgeons 0278-2391/93/5112-0010$3.00/0
1338
1339
UMINO ET AL and attempted to characterize trigeminal neuralgia in elderly patients during CBZ administration.
Methods PATIENTS Five elderly patients with trigeminal neuralgia, 66 to 77 years old, gave their informed consent and were assessed. No patients had a history of any other neurologic diseases. No evidence of organic disturbances of the face, maxillary sinus, mandible, or temporomandibular joint were found on radiographic examination. The diagnosis of trigeminal neuralgia was made on the basis of the history and diagnostic criteria for trigeminal neuralgia." The patients' characteristics are shown in Table I. All patients refused neurosurgical treatment, neurectomy, or alcohol nerve block, preferring CBZ below the dose inducing side effects. They agreed to pain relief by local anesthesia when pain increased. SYMPTOMS BEFORE TREATMENT AND DETERMINATION OF CBZ DOSAGE
Case 1 The patient had been treated with 800 mg ofCBZ per day for I month at another hospital before coming to our hospital, but the drug was suspended because of severe side effects. Table 1.
Before treatment, extremely severe pain was provoked by talking, eating, touch, and vibration. The frequency of pain attacks reached 15 to 20 times a day. Daily life was extremely compromised by the paroxysmal pain. After treating the patient with 200 mg of CBZ twice a day for I week, she was given 200 mg of CBZ three times a day for an additional week. Severe pain attacks were relieved, but pain relief was incomplete. Therefore, 200 mg of CBZ was given four times a day, but severe dizziness, difficulty in walking, and ataxia developed. Two hundred milligrams of CBZ, three times daily, or less occasionally, was selected as the daily dose.
Case 2 Before treatment, the frequency of pain attacks was 15 times a day, and paroxysmal pain was induced by talking, eating, and touch. This led to impaired activities of daily living, such as difficulty in conversation and food ingestion. When 200 mg ofCBZ was administered two times a day for 2 weeks, the severe attacks were reduced, but pain was not relieved completely. Accordingly, 200 mg ofCBZ was given three times a day for a week, but drowsiness, dizziness, generalized weakness, and nausea resulting in difficulty in eating developed. Therefore, 200 mg ofCBZ (occasionally less), two times daily was chosen as the therapeutic regimen.
Case 3 The frequency of pain attacks in this patient was 14 or 15 a day before therapy. Extremely severe pain was induced by talking, eating, touch, and tongue movements. In daily life, conversation and food ingestion were difficult because of the paroxysmal pain. The patient was initially treated with 100 rng of CBZ twice a day for 2 weeks and then 200 mg of CBZ
Clinical Characteristics of the Five Patients With Trigeminal Neuralgia
Sex/Age (yr)
Weight (kg)
Duration of Trigeminal Neuralgia Prior to Diagnosis (mo)
F/66
56
18
R·I1
Right upper lip
2
MI73
65
4
R-llI
3
F/75
45
3
L-llI
4
Ff77
43
6
R-lll
Gingiva around the right mandibular molar teeth Gingiva around the left mandibular molar region Right margin on tongue
5
F/7l
46
3
R-I1
Right upper lip
Talking, tongue
Patient No.
Location of Trigeminal Neuralgia
Trigger Zone
Treatment Prior to CBZ
Provoking Factor of Pain
Frequency of Pain Attack
Talking. eating, touch, vibration Talking, eating. touch
15 - 20 times/day (great) More than 15 times/day (great)
CBZ
Angina pectoris
Dental treatment, local anesthesia
Diabetes mellitus, hypertension
Talking, eating, touch, tongue movement
14 or 15 times/day (great)
None
None
Nitroglycerin at anginal attack Hypoglycemic agent (drug name unknown), propranolol None
Talking, eating, tongue
15 - 20 times/day (great) More than to times/day (frequent)
None
None
None
Acupuncture
Hypertension
Nifedipine
movement
movement,
Complicating Diseases
opening mouth
Abbreviations: R, right; L, left; II, maxillary division trigeminal nerve; III, mandibular division trigeminal nerve.
Medication
CARBAMAZEPINE AND TRIGEMINAL NEURALGIA
1340 additionally twice a day for I week. Occasional pain attacks developed during treatment. Consequently, 200 mg ofCBZ was given three times a day. After taking CBZ at this dose, the patient developed difficulty in walking, dizziness, and generalized weakness. Accordingly, 200 mg or less of CBZ twice daily was prescribed as the daily dose.
Case 4 The frequency of pain attacks reached 15 to 20 times a day in this patient. Provoking factors were talking, eating, and tongue movements. It was difficult for the patient to consume anything except canned liquid meals. An initial dose of 100 mgofCBZ was given twiceaday for 2 weeks. Although the pain attacks diminished, the patient complained of dizziness, nausea, appetite loss, gastrointestinal disorders, and difficulty in walking. CBZ 50 mg twice or occasionally three times a day was chosen as the dose.
Case 5 The frequency of pain attacks was approximately 10 times a day in this patient. Paroxysmal pain was provoked by tongue movements, opening the mouth, and talking. CBZ, 100 mg, was initially given once a day for a week. Since complete pain reliefwas not obtained, 100 rng ofCBZ was given twice a day. The patient developed difficulty in walking, dizziness, and generalized weakness. Therefore, 50 mg of CBZ twice a day was selected as the daily dose. CBZ doses were occasionally adjusted further when side effects or hematologic abnormalities developed in individual cases.
MEASUREMENT OF PAIN INTENSITY A visual analogue scale (VAS) consisting of a 100mm horizontal straight line, the left end representing "no pain" and the right end the "worst pain," was used to determine pain intensity before therapy. Patients were then requested at the time of blood sampling to indicate on the VAS the worst pain intensity experienced during the preceding week, and this was compared with the worst pain reported before therapy. RECORDING OF PAIN ATTACKS At the time of blood sampling, the patients were instructed to indicate the frequency of average daily pain attacks for the preceding weeks as great (over 15 til11~s a day), frequent (10 to 14 times a day), moderate (five to nine times a day), few (one to four times a day), or none (zero times a day). RECORDING OF PROVOKING FACTORS AND SIDE EFFECTS Provoking factors and side effects were investigated at the time of interview every 2 weeks. RECORDING OFTHE CBZ DOSAGE
MEASUREMENT OF SERUM CBZ CONCENTRATIONS Four milliliters of venous blood were collected between IO AM and 12 AM. These samples were immediately centrifuged for 20 minutes at 4°C, and the sera were separated. Total serum CBZ concentration was measured by the fluorescence polarization immunoassay method 10 using a TDX Drug Assay-Carbamazepine Kit (Abbott Laboratories Diagnostic Division, North Chicago, IL). The coefficient value of this kit was less than 3.9%, and sensitivity was 0.5 pg/mL. The average recovery was IOI% ± 1.3%, and the rate of cross-reaction to CBZ-IO,II-epoxide (CBZ-E) was 13.2%. A TDX Fluorescence Polarization Analyzer (Abbott Laboratories Diagnostic Division) was used as the measuring instrument. Patients all took CBZ upon awakening on the day of blood sampling. BLOOD EXAMINATION Measurement of red blood cells, white blood cells, hemoglobin, hematocrit, and a differential white cell count were performed using an automated hematology analyzer (Coulter Counter T660, Coulter Techtronics, Inc, Hialeah, FL). Blood chemistry studies were performed using an automatic analyzer (Hitachi model 7150, Japan). These examinations were performed at the same time serum CBZ concentrations were measured.
Patients were requested to record daily CBZ intake at home. The daily CBZ doses for the preceding week were recorded at the time of blood sampling. VAS recording, measurement of serum CBZ concentration, and blood studies were performed approximately every 2 or 3 months after initiation of CBZ therapy.
Results
Case 1 Fluctuations in pain were observed after CBZ therapy. Severe pain persisted after 2 months, despite high serum CBZ concentrations. After 8 months of using CBZ, complete pain relief was obtained. After 12 months of using CBZ, pain intensity and the frequency of pain attacks again increased. The effects of CBZ were inadequate despite the high serum concentrations at 2 and 12 months. At these times, local anesthesia with 2% lidocaine was administered in the pain-provoking area. After 12 months, complete pain relief continued for another 5 months. After that, the patient consented to neurosurgical treatment and underwent a microvascular decompression procedure. Side effectsand hematologic abnormalities were transient (Table 2).
1341
UMINO ET AL
Table 2.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 1 Months After CBZ Treatment 4
CBZ dose (rng/d) Serum CBZ concentration (l'g/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain Side effects Abnormal hematologic findings Other treatment
12
6
16
14
19
600 10.9
400 8.1
400 6.9
300 5.8
600 13.1
500 9.6
400 6.4
70
8
8
0
71
0
0
16
Frequent
Few
Few
None
Frequent
None
None
Few
Talking, eating, touch Dizziness
Eating
Eating. washing face
Talking. eating. touch
400 9.4
Talking. eating
Leukopeniadecreased serum calcium
Leukopenia
Local anesthesia
Local . anesthesia
Case Z
with 2% lidocaine was given in the provoking area a few times, the patient was subsequently unable to come for further injections because of hospitalization for treatment ofa gallstone. During this period the patient continued to take 400 mg of CBZ. After 15 months, pain intensity and attacks gradually decreased despite the low serum CBZ concentrations. Side effects were transient; there was transient leukopenia, elevation of 'Y-guanosine triphosphate, glutamine-oxaloacetic transaminase, and glutamic-pyruvic transaminase among the hematologic findings (Table 4).
Pain intensity and attacks decreased in response to CBZ, compared with pretreatment levels. However, although serum CBZ concentrations remained stable at between 8.0 and 10.2 pg/mL, pain intensity fluctuated after 4 and 8 months. During this period there were instances of resistance to CBZ, and 2% lidocaine was administered in the provoking area for pain relief. There were transient side effects and hematologic abnormalities (Table 3).
Case 3 Case 4
Pain intensity and attacks were relatively well controlled after 2 months of CBZ, despite the low serum concentrations. After 4 months, pain intensity and attacks increased and inadequate analgesia persisted for several months despite relatively high serum concentrations. Although during this time local anesthesia
Table 3.
Despite the stable CBZ serum concentrations, relatively weak fluctuations in pain intensity were recognized. Pain intensity and attacks gradually decreased, becoming "slight" after to months ofCBZ. However, pain again became intense 13 months after CBZ had
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 2 Months After CBZ Treatment 2
CBZ dose (mg/d) Serum CBZ concentration (Jlg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain Side effects Abnormal hematologic findings Other treatment
6
4
II
300 8.0
400 9.6
400
10.2
400 9.3
10
45
20
40
16
Few Touch, brushing Drows iness
Moderate Talking, eating, shaving
Few Talking, brushing
Moderate Talking,
Fcw Eating
Increased eosinophils Local anesthesia
eating Dizziness
400 9.2
1342 Table 4.
CARBAMAZEPINE AND TRIGEMINAL NEURALGIA
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 3 Months After CBZ Treatment 15
4
CBZ dose (mg/d) Serum CBZ concentration (pg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain
17
400
200
400 7.4
300 7.3
400
2.8
9.2
400 1.5
9 Few Talking, eating
51
53
48
33
17
Moderate Swallowing, talking, eating
Frequent Talking, eating, touch
Moderate Talking. eating, touch
Moderate Talking, eating
Few Eating
Side effects
2.8
Dizziness
Abnormal hematologic findings
Decreased serum calcium
Other treatment
Local ane~thesia
Leukopenia, elevated "Y·G T P, GPT, and GOT
Abbreviations: GTP, guanosine triphosphate; GPT, glutamic-pyruvic transaminase; GOT, glutarnic-oxaloacetic transaminase.
been started, although during this period stable but low serum CBZ concentrations were maintained. Side effects and hematologic abnormalities were transient (Table 5).
Case 5 Pain intensity and attacks gradually decreased after CBZ therapy and, by 4 months, complete pain relief was obtained and the patient no longer required medication. Transient, severe leukopenia developed, but there was subsequently a return to normal levels (Table 6). Discussion
Several methods of pain assessment have been used to evaluate clinical pain and determine the effect of Table S.
analgesic drugs, although the problems in measurement are also well recognized. II The pain score and Verbal Rating Scales(VRS) frequently have been used to assess pain in trigeminal neuralgia and the therapeutic effects ofCBZ,12,'3 because the pain score and VRS are more appropriate than the VAS to assess pain magnitude in cases of paroxysmal and refractory pain such as in trigeminal neuralgia. These tests evaluate three elements: intensity, frequency, and duration, whereas VAS is a simple, quantitative, and continuous scale, and is appropriate to assess pain intensity.I':" Therefore, if the focus of pain assessment is only pain intensity, it is possible to use the VAS to assess pain in trigeminal neuralgia. 15 In addition, it was too difficult for our elderly patients to maintain a long-term pain score diary. For these reasons, VAS was used to assess pain in the present study. At the same time, the frequency of pain attacks also was recorded with a stepwise scale.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 4 Months After CBZ Treatment
CBZ dose (mg/d) Serum caz concentration (pg/mL) Pain intensity (mm) Frequency of pain attack Provoking factors of pain
100
150
100
100
100
3.7
4.9
3.8
3.0
3.4
30
16
Moderate Swallowing, eating, cough
Few Talking, rinsing, yawning
18 Moderate Talking, eating
7 Few Eating
6 Few Washing face
Side effects Abnormal hematologic findings
II
9
4
Leukopenia
Leukopenia increased, segmented
Gastrointestinal disorders Leukopenia decreased, lymphocytes
13
100 3.2 36 Moderate Washing face, jaw movement
1343
UMINO ET AL
Table 6.
Serum Carbamazepine Concentration, Pain Intensity, and Clinical Data in Case 5 Months After CBZ Tre atment 10
4
CI3Z dose (mg/d) Serum CBZ concentration
100 1.0
0 0.5
0 0
0 0
44
16
Mod erate Touch, jaw movement
Few Touch
0 None
0 None
0 Non e
100 1.6
(~g/mL)
Pain int ensity (mm) Frequency of pain attack Provo king factors of pain Side effects Abnormal hematologic findings
The therapeutic effects ofCBZ were correlated with the serum CBZ concentration. Since there is a linear relationship between the dose and serum concentration of CBZ,12 the higher the serum CBZ concentration, the better the expected therapeutic effects. Tomson et al 12 reported that the optimal effect was seen at CBZ levels between 5.7 and 10.1 IlgfmL. In this study serum CBZ concentrations in patients 1,2, and 3 (except for one time period) were within the effective range reported by Tomson et al." However, in these cases, even when the serum CBZ concentration was maintained within a relatively high range, there were periods in which pain intensity increased . On the other hand, there were periods in which pain was relatively well controlled even though the serum CBZ concentration was relatively low. Such fluctuations in pain intensity show that the CBZ response curve varies from period to period even within an individual. Unstable CBZ response curves are due to instability and spontaneous variations in pain in trigeminal neuralgia . The pain magnitude in trigeminal neuralgia is determined by a balance between spontaneous variations in pain and serum CBZ concentrations while on CBZ therapy. When the spontaneous variation of pain is in the active period, response to CBZ decreases. Taylor and Brauer" also have indicated that resistance to CBZ is induced by longterm administration ofCBZ. On the other hand, when the spontaneous variation in pain enters an inactive period, even low-serum CBZ concentrations are effective. Autoinduction by CBZ during long-term administration is another cause of fluctuations in pain. Autoinduction of liver microsomal enzymes during longterm .drug administration leads to shortening of the half-life of CBZ, reduced serum concentrations, and lessened therapeutic effects.":" In the present study, only one case (no. 3) showed a decrease in serum CBZ concentration (1.5 and 2.8 Ilg/mL on a 400-mg daily dose of CBZ for 15 and 17 months, respectively) in which the discrepancy between dose and serum concentration might have been caused by autoinduction.
Leukopenia
The primary metabolite of CBZ, CBZ-E, also may be a factor influencing therapeutic effect.18 CBZ-E itself has potent therapeutic effectson trigeminal neuralgia.19 CBZ-E levels are correlated with the doses and serum concentrations of CBZ.20 Bertilsson and Tomson" have shown that the serum CBZ-E concentration is between 10% and 50% of the serum CBZ concentration. Monaco et al,22 on the other hand, postulated that the plasma CBZ-E concentration fluctuated markedly, independent ofCBZ level, during long-term administration. Although we did not measure serum CBZ-E concentrations in the present study, enhanced CBZ-E formation may have occurred during the longterm administration in our cases. It is likely that CBZE formation may have been a cause of pain fluctuation. In our cases there were considerable interindividual differences in response to CBZ. In case 4, pain was relatively well controlled without disturbance of the patient's daily life despite CBZ concentrations below the most effective levels reported by Tomson et al." In case 5, the patient also responded well to extremely low serum CBZ concentrations, with pain eventually disappearing spontaneously. In cases I, 2, and 3, on the other hand, higher serum CBZ concentrations were required than in cases 4 and 5 to obtain well-controlled pain relief. The interindividual differences in response to CBZ may be due to differences in the severity of trigeminal neuralgia, pharmacokinetics, and methods of pain assessment. However, it was difficult to determine the main cause of the interindividual differences in response to CBZ. In any case, interindividual differences in response to CBZ appear to be frequent in elderly patients. As pain intensity fluctuates in trigeminal neuralgia, satisfactory pain relief can be obtained temporarily even with CBZ doses restricted because of side effects. Therefore, it is essential to observe spontaneous variations in pain intensity and the therapeutic effect of CBZ during long-term administration. It is recommended that serum CBZ and CBZ-E concentrations be monitored while recording pain intensity periodically in elderly patients. If such monitoring is per-
1344
DISCUSSION
formed, it is not only possible to know the response to CBZ, the fluctuations in the rhythm of the pain, and the characteristics of the pain, but also to avoid an overdose of CBZ, to make adjustments to the CBZ dose, and to decide on indications for neurosurgical procedures or alcohol nerve block. Acknowledgment The authors wish to acknowledge Dr Hiroyasu Akatuka, Division of Biochemistry, Mitsubishi Yuka Bio-Clinical Laboratories, Inc (Tokyo, Japan) for cooperation in measurement of the serum CBZ concentrations.
References I. B10mS: Trigeminal neuralgia: Its treatment with a new anticonvulsant drug (G32883). Lancet 1:839, 1962 2. B10m S: Tic douloureux treated with new anticonvulsant, Experiences with G32883. Arch Neurol 9:285, 1963 3. Rasmusse P, Riishede J: Facial pain treated with carbamazepin (Tegretol). Acta Neural Scand 46:385, 1970 4. Sillanpa M: Carbamazepine pharmacology and clinical use. Acta Neurol Scand 88:115, 1981 (SuppI64) 5. Killian JM, Fromm GH: Carbamazepine in the treatment of neuralgia, Use and side effects. Arch Neural 19:129, 1968 6. Zakrewska JM: Medical management of trigeminal neuralgia. Br Dent J 168:399, 1990 7. Zakrewska JM, Patsalos PN: Drugs used in the management of trigeminal neuralgia. Oral Surg Oral Med Oral PathoI74:439, 1992 8. Taylor JC, Brauer S: long-term treatment of trigeminal neuralgia with carbamazepine. Post Med J 57:16, 1981
9. Bell WE: Orofacial Pains, Classification, Diagnosis, Management (ed 4). Chicago, Il., Year Book, 1989, p 377 10. McGregor AR, Crookall-Greening JO, Landon J, et al: Polarisation fluoraiminunoassay of'phenytoin. Clin Chim Acta 83: 161,1978 I I. Chapman CR, Casey Kl., Dubner R, et al: Pain measurement: An overview. Pain 22:1, 1985 12. Tomson T, Tybring G, Bertilson L, et al: Carbamazepine therapy in trigeminal neuralgia, Clinical effects in relation to plasma concentration. Arch Neural 37:699, 1980 13. Fargo F: Trigeminal neuralgia: Its treatment with two new carbamazepine analogues. Eur Neural 26:73, 1987 14. Kremer E, Atkinson JH, Ignelzi RJ: Measurement ofpain: Patient preference does not confound pain measurement. Pain 10: 241,1981 15. Sharav Y, Benoliel R, Schnarch A, et al: Idiopathic trigeminal pain associated with gustatory stimuli. Pain 44:171, 1991 16. Eichelbaum M, Ekbom K, Bertilsson L, et al: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin PharmacoI8:337, 1975 17. Morsell Pl., Frigerio A: Metabolism and pharmacokinetics of carbamazepine. Drug Metab Rev 4:97, 1975 18. Bertilsson L: Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet 3:128, 1978 19. Tomson T, Bertilsson L: Potent therapeutic effect ofcarbamazepine-Hl.l l-epoxide in trigeminal neuralgia. Arch Neural 41: 598, 1984 20. Elyas AA, Patsalos PN, Agbato OA, et al: Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-Ht.l l-epoxide in serum of children with epilepsy. Ther Drug Monit 8:288, 1986 21. Bertilsson L, Tomson T: Clinical pharmacokinetics and pharmacological effects of carbarnazepine and carbarnazeplneIO,II-epoxide. C1in Pharmacokinet 11:177, 1986 22. Monaco F, Riccio A, Benna P, et al: Further observations on carbamazepine plasma levels in epileptic patients. Neurology 26:936, 1976
J Oral Maxillofac Surg 51 :1344-1345. 1993
Discussion Long-Term Observation of the Relation Between Pain Intensity and Serum Carbamazepine Concentration in Elderly Patients With Trigeminal Neuralgia John R. Zuniga, DMD, MS, PHD UniversityofNorth Carolina School ofDentistry, Chapel Hill, NC
Carbamazepine (Tegretol; Basel Pharmaceuticals, Summit, NJ) is the preferred drug for the initial and long-term management of trigeminal neuralgia (TN). Its mechanism of action is unknown; however, within the spinal trigeminal nucleus it increases seizure threshold, inhibits the release of excitatory neurotransmitters, and inhibits synaptic transmission. The anti neuralgic effect of carbamazepine is rapid, but a dose of 200 to 1600 mg daily is often required to gain good pain control. Side effects (21%)are dose-dependant and transient, occurring mainly during initial therapy, frequently in the elderly, and after a rapid increase in dose. Thus, most clinicians titrate the drug slowly to the occurrence of pain relief or side effects by changing the dose, 200 mg at a time, every 2 to 3 days. More than half of the patients with TN (56%) respond to long-term carbamazepine therapy. Serious hematologic and hepatotoxic side effects may occur during long-term therapy and necessitate monthly screening.
The goal of this study was to examine the relationship between the subjective pain intensity of TN and serum carbamazepine (CBZ) concentration in five patients over a 2to 19-month treatment period. The hypothesis was that TN pain relief is related (linearly) to serum CBZ concentration and that monitoring serum CBZ is a valuable tool in the clinical management of TN. However, there are no statistical data presented to support this hypothesis. To show these facts, the CBZ dose (rng/d), serum CBZ concentration (j.lg/mL), pain intensity (millimeters), and pain frequency (converted from descriptions provided in the text) data from Tables 2 through 6 were subjected to parametric and nonparametric statistical analysis. Multivariate linear regression was used to describe the relation between serum CBZ concentration and pain intensity and frequency, and Spearman correlation analysis was performed to evaluate the association between dose, pain frequency and intensity, and the regression coefficient ofserum CBZ concentrations. The level ofconfidence was set at 0.05. The results are presented in Table I, and they show that there was no significant relationship between serum CBZ concentration and pain intensity (P = .385, r = .23) or pain frequency (P = .748, r = .12). There was a significant relationship, however, between CBZ dose and serum CBZ concentration (P = .00 I, r = .8l). These findings can be explained by review ofthe literature. It is true that Tomson et al' demonstrated a positive rela-