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The effects of tramadol on pain relief, fast EEG-power spectrum and cognitive function in elderly patients with chronic osteoarthritis (OA)
Acute Pain (2006) 8, 55—61
The effects of tramadol on pain relief, fast EEG-power spectrum and cognitive function in elderly patients with chronic osteoarthritis (OA) E. Freye a,∗, J.V. Levy b a
Clinic of Vascular Surgery and Renal Transplantation, Heinrich-Heine-University Clinics of D¨ usseldorf, Moorenstrasse, Germany b Department of Pharmacology & Physiology, University of the Pacific, Webster Street, San Francisco, USA Received 9 November 2005 ; received in revised form 8 March 2006; accepted 10 March 2006 Available online 18 May 2006 KEYWORDS Tramadol; Pain; Elderly; Osteoarthritis; Electroencephalogram; Cognitive function testing (SCAG)
Summary Pain and cognitive impairment in the elderly patient with osteoarthritis (OA) often is managed inadequately with common NSAIDs. We therefore evaluated the opioid-like agent tramadol, preportedly also acting as a monaminergic reuptake inhibitor. Patients (75 years ± 7S.D.; 17 female, 2 male) with chronic OA of the knee, elbow, shoulder and hip complaining of acute pain were given two 50 mg/70 kg oral doses of tramadol 30 min apart. Before, during and 2 h after medication, the following parameters were measured: 1. Heart rate (HR) and blood pressure (BP). 2. Visual analogue scaling (VAS) of pain associated with movement. 3. Relative changes in the EEG-power spectra (␦, , ␣, ) to control, over a 60 s period. 4. Cognitive function using the Sandoz Clinical Assessment Geriatric scale (SCAG). Patients experienced a significant (p < 0.01) reduction in VAS assessed pain from 7.8 ± 2.0 to 2.2 ± 0.5. In the EEG, power in ␦ (0.5—3 Hz) dropped from 50 to 35% (p < 0.005), ␣ (8—13 Hz) increased from 12 to 25% (p < 0.001) and  (13—30 Hz) from 23 to 37% (p < 0.001). There was an improvement (p < 0.001) in both severities of depression and cognitive function scoring. There were no significant changes in HR or BP.
∗
Correspondence to: E. Freye, Deichstrasse 3a, 41468 Neuss-Uedesheim, Germany. Tel.: +49 2131 369 4396. E-mail address: [email protected] (E. Freye).
1366-0071/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2006.03.001
56
E. Freye, J.V. Levy In addition to pain relief, tramadol also improved mood, the ability to perform tasks and reversed disability in cognitively impaired elderly. Subsequent to this pilot trial further studies of tramadol in the elderly are warranted. © 2006 Elsevier B.V. All rights reserved.
1. Introduction Pain in the elderly patient with osteoarthritis (OA) is difficult to manage, because of the stoic attitude of patients, and the possible interaction with other agents often taken by the elderly. Acetaminophen and NSAIDs often are considered agents of choice when peripherally mediated pain is present as in osteoarthritis. However, these agents tend to induce gastrointestinal lesions or hepatic disorders, especially when taken over a long period of time [1,2]. When using newer COX-2 inhibitors (e.g. celebrex), which show a reduced incidence in the formation of gastric lesions [3,4], new safety guidelines have to be observed and they should be avoided in high-risk cardiovascular patients. For instance similar to non-selective NSAIDs, they cause sodium retention by inhibiting COX-2, which occasionally can lead to peripheral oedema, increase in blood pressure and congestive heart failure [5,6]. Therefore, patients with renal insufficiency, hypertension or patients treated with an angiotensinconverting enzyme (ACE) inhibitor and patients using angiotensin receptor antagonists, potassiumsparing diuretics or have decreased renal perfusion should not be given an NSAID or COX-2 inhibitor therapy. Potent CNS-acting analgesics such as opioids tend to induce a marked sedation with lethargy or even delirium [7—9] in the elderly. This is either due to a reduced metabolism of the liver or renal insufficiency resulting in higher plasma concentrations of the opioid [10]. Also, opioids interact with antihypertensive agents (e.g. Ca2+ -channel blockers, -blockers, ACE-inhibitors, etc. [11]), which either results in a potentiation of the sedative effect of the opioid or results in an additive effect of the blood pressure lowering agent [12]. Therefore, highly potent agents like transdermal fentanyl, oral oxymorphone and oxycodone are not considered drugs of choice especially when the patient is opioid na¨ıve [13,14]. While cognitively impaired elderly patients tend to under report pain, their discomfort is no less important than those of cognitively intact patients. Consequently, an analgesic drug of choice for elderly patients with OA is one with the lowest sideeffects profile, including lack of impairing cognitive functions. Tramadol [1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclo-hexan-1-ol] an opioid with
intermediate potency is a suitable choice for the elderly because it is characterized by less side-effects, little interaction with other drugs and has negligible abuse potential [16—18], with a wide margin of safety [19]. Since tramadol also acts as a monaminergic reuptake inhibitor [20,21], possible additional sedative or desynchronizing effects on the EEG were evaluated. Special attention was focused on changes of cognition and attention deficiency, symptoms typically seen in the elderly patient.
2. Materials and methods After obtaining written informed consent and, after approval by the local Human Subjects Committee of the University Clinic, 19 patients (mean age 75 years ± 7S.D.; 17 female, 2 male) with chronic OA of the knee, elbow, shoulder and hip were enrolled in the study. They complained of acute pain during movement and insufficient pain relief with NSAIDs. They were given two doses of 50 mg of an oral solution administered 30 min apart while being in a supine position. Titration of two doses of 50 mg was considered important in order to detect side-effects as early as possible and demonstrate a potential dose-related effect on the electroencephalogram. Before the first dose, prior to, and 30 min after the second dose of the drug, the following parameters were measured: 1. Heart rate (HR) and blood pressure (BP) using a non-invasive pressure monitoring device in the upper extremity. 2. Visual analogue scaling (VAS) of dynamic pain using a metric scale between 0 (no pain) and 10 (unbearable pain). Pain was evaluated while patients were asked to move their affected joint as requested by the investigator. 3. Electroencephalographic activity to determine any potential sedative effect of the opioid. Three Ag/AgCl stick-on electrodes positioned at Fp1 -A1 or Fp2 -A2 , with one electrode on position FpZ as reference (ten—twenty system), were used to record the power spectra in the three EEG frequency bands: ␦ (0.5—3 Hz), (3—8 Hz), ␣ (8—13 H7) and  (13—30 Hz), which can be used to demonstrate changes of vigilance induced by a centrally active agent. Original EEG signals
The effects of tramadol on pain relief from a pre-amplifier were entered into an EEGrecorder (Lifescan® , Diatek, San Diego, USA), which analysed the power (V2 ) in the various EEG-power bands. From the EEG recorder, data were entered into a laptop computer (Kaypro® 2000) with a system software which computed the absolute power within the various frequency bands over a time period of 60 s. Results were printed out on a built-in printer with appropriate frequency response features. Specification and operational features were specifically designed for continuous EEG measurement using an automatic electrode impedance check <5 k of 45 db dynamic range. 4. Individual grading of cognitive function was made using the Sandoz Clinical Assessment Geriatric scaling (SCAG). This permitted analysis of various items related to social factors such as vitality, vigilance and cooperation [22]. Evaluation of SCAG using a total of 18 items was considered appropriate to evaluate the cognitive, affective, social and some physical properties using an intensity analogue scale (1, nonexistent; 2, very weak; 3, weak; 4, weak to medium; 5, medium; 6, moderately severe; 7, severe). An independent observer assessed rating. Thus, assessment was obtained for items such as recent memory, depression, anxiety, loss of orientation, quick-temperedness, unstable mood, loss of motivation, irritability, hostility, indifference to environment, unsociability, uncooperative behaviour, personal hygiene, tiredness, loss of appetite and vertigo. These are used as major measures in evaluating the degree of dementia and because SCAG had been shown to be a reliable tool in evaluating presenile and senile dementia [23,24] and especially useful to determine the efficacy of a specific therapy [25]. This assessment tool was also considered a reliable instrument for detecting beneficial and side-effects of tramadol. It was felt that such measurements were of importance in the present population, since the use of an atypical centrally acting analgesics results in further deterioration of vigilance and concentration in the elderly who already may manifest deficiencies in cognition and attention or who already show symptoms of dementia [26]. Since these measurements were obtained before and after tramadol for the same subject, each subject served as their own control. The duration of action of tramadol is around 4—6 h. Following completion of the study, and once the test medication was proven effective, the patient was changed to
57 a slow release formulation of the agent to assure long-term efficacy.
3. Statistical analysis Before starting the study, a priori statistical power analysis was done. This was necessary to calculate the sample size (number to treat), necessary for demonstration of statistical significance in the study. Power analysis demonstrated pragmatic constraints for the investigation. In order to detect the maximum possible sample size, compromised power analysis was performed. Power was calculated using the standard deviations in the different EEG-spectra of a previous study in patients undergoing treatment with tramadol for reversal of migraine pain [27]. Computation of sample size for paired t-test yielded a number 18 subjects necessary for having a 95% power to detect a before—after difference at a significance level (˛) of 0.05 (two-tailed). For computation of relative power changes, each EEG-power spectrum of the control period was set at 100 and the changes at the given endpoints were compared to control. Parameters at different stages after tramadol were compared with the period before the agent using Friedman’s test for repeated measures of analysis of variance of ranks. The two-sided Student—Newman—Keuls test for multiple comparisons was used to calculate significance levels compared to control. In addition, total scoring of all items in SCAG was compared to pre-drug control. A value of p < 0.05 was considered statistically significant. Data are shown as mean value ± standard deviation (S.D.).
4. Results Following two doses of 50 mg/70 kg of tramadol, elderly patients experienced a significant (p < 0.01) reduction in pain of their osteoarthritic joint(s) (Fig. 1). From a mean control VAS of 7.8 (±2.0S.D.), pain intensity dropped to a mean of 2.2 (±0.5S.D.) suggesting a positive analgesic effect of the agent. It should be noted, that a total dose of 100 mg/70 kg and not a single dose of 50 mg/70 kg was needed to produce therapeutic effects. In addition to the reduction in pain, patients demonstrated significant changes in their EEG (Fig. 2). In the electrical cortical activity, power of the ␦-band of the EEG (0.5—3 Hz) dropped from a relative 50 to 35% (p < 0.01), while power in the ␣band (8—13 Hz) increased from a relative 12 to 25% (p < 0.005). Power in the fast frequency -domain
58
Fig. 1 Visual analogue scaling (VAS) 0—10 in elderly patients with osteoarthritic pain before and after tramadol 100 mg/70 kg (mean ± S.D.).
(13—30 Hz) increased from a relative 23 to 37%. This was highly significant (p < 0.001) when compared to the period before tramadol (Fig. 2). The Sandoz Clinical Assessment Geriatric scoring for grading of cognitive function indicated that there was a high score in the intensity of symptoms before tramadol was administered. The high score revealed impairment in cognitive function such as
E. Freye, J.V. Levy
Fig. 2 Grand mean changes of power in EEG spectra ␦ (0.5—3 Hz), (3—7 Hz), ␣ (7—13 Hz) and  (13—30 Hz), before and after incremental doses of tramadol. Note the increase of power in the fast ␣- and -domain.
derangement in thinking, an affective disorder, as well as impairment in vigilance and vitality, all of which attributed to the high global score in cognitive and cerebral dysfunction. On the other hand, items such as loss of independence and personal hygiene had less impact on the global cognitive dysfunction score. While the total score for all items
Fig. 3 Summary of selected items in depression scaling and evaluation of cognitive function, using a polar coordinate system where each data point is specified by a radius from the centre.
The effects of tramadol on pain relief was 80 ± 11 before tramadol, it decreased to a mean of 55 ± 14 after the tramadol. The scores for severity of depression and reduced cognitive function in this elderly patient population revealed a highly significant (p < 0.001) improvement following the agent (Fig. 3). There was no significant increase in heart rate and blood pressure following drug treatment.
5. Discussion Treatment of OA in elderly patients with tramadol produces a sufficient relief of pain. This analgesia is not mediated via a blockade of peripheral nociceptors, which in osteoarthritis are the source of nociceptive afferents. Contrary to acute pain seen with acute stage of inflammation in rheumatoid arthritis, in chronic osteoarthritis pain has sensitized the spinal tract [28]. This explains in part the relative ineffectiveness of peripherally acting analgesics such as NSAIDs. Therefore, pharmacologic treatment of pain associated with OA in the elderly should also consider a centrally acting analgesic [11] a concept, which has emerged in modern pain therapy. While opioids in a young patient population is characterized by a small incidence in sideeffects, in the elderly one has to consider a potential interaction with other agents. This may result in pharmacologically related side-effects, which may account for a 56% incidence of delirium [7,8,29]. Therefore, only agents characterized by a high margin of safety [30] but still being effective in managing the arthritic pain should be considered. In this regard, tramadol seemed a suitable agent because it had been shown to be affective in arthritic pain [31] and at the same time shows less side-effects than other opioids [19]. Because nausea is considered a major side-effect shortly after intake of tramadol [16], special care was taken for its avoidance by letting the patient lie down in a supine position for 1 h. While the beneficial antinociceptive effect can be attributed partly to an opioid action of tramadol, selective monaminergic reuptake inhibition [20,21] has to be considered as another mode of action. This would result in increasing activity of the descending pain-inhibitory afferents [32]. Tramadol therefore demonstrates an antinociceptive effect via two synergistic mechanisms, a feature of advantage in patients suffering from OA pain. The monaminergic reuptake inhibition is also of advantage in reversing dementia symptoms. It is generally accepted that the cause of dementia is the chronic release of the excitatory amino acid glutamate, an ensuing increase of influx of Ca2+ -ions and a reduced release of transmitters
59 from neuronal cells, followed by apoptosis [33]. And since it is recognized that essential neurotransmitter release are involved in normal CNS functions, persons with a variety of cognitive and affective disorders may show deficient levels of dopamine, norepinephrine and acetylcholine. Tramadol seems to reverse such effects, especially since the reduction in neuronal transmitter release is opposed by the monaminergic reuptake mechanism of tramadol resulting in restoration of function in cerebral areas normally depressed or inactive [33]. This assumption is supported by experimental data where tramadol administration resulted in an increased release of monaminergic transmitters such as dopamine, norepinephrine and serotonin in the synaptic cleft [15,34,35]. While dopamine and norepinephrine activity affects arousal and attention, dopamine is also thought to have a role in language function. Thus, dopaminergic agents, as been shown in small studies in selected subjects, were able improve alertness or ‘‘arousal’’, attention, concentration, language skills and memory [27,37]. Given these observations, an agent like tramadol increases the levels of the deficient transmitters or mimics transmitters where these natural neurotransmitters are lacking. In addition, the present data in the EEG-power spectra support such concept since improvement of alertness, arousal or attention, was reflected in an increase of power in the fast -band. Contrary to the common observation that opioids result in an increase in power of the slow ␦- and -domain, tramadol significantly reduced power in the slow ␦-band. Such changes can be interpreted as EEG desynchronisation normally seen with an increase in vigilance and attention [36]. Such tramadol-related desynchronisation was also seen in patients undergoing inhalational anesthesia resulting in lightening of the depth of anesthesia [37,38]. Also, unlike a potent analgesic like alfentanil, tramadol induces a dose-related increase in amplitude height of the somatosensoryevoked potential of the EEG in non-anaesthetized canines [39], all of which underlines a non-opioid activity of the agent. Also, contrary to other opioids of similar potency, tramadol has a low risk of addiction [40—42], development of tolerance after long-term administration [43] and has a low incidence on respiratory depression [44,45]. There is less inhibition of gastrocecal transit time, and it has a reduced miotic effect [46,47]. Such absence of opioid-related effects is explained by opioid receptor binding studies, where affinity of tramadol was 1/1000-fold less than that of morphine [48]. From these data it can be concluded that the analgesic potency of tramadol is related partly due to its opioid binding capacity
60 of the metabolite M1 [15] but mostly due to its monaminergic reuptake mechanism, which affects the descending inhibitory pain pathways [20,49]. The mechanism of this beneficial activation of the descending inhibitory system is the same mechanism that also contributes to a reduction of cognitive dysfunction often observed in the elderly patient population. In summary, the opioid tramadol was able to reduce acute pain in elderly patients with chronic osteoarthritis. In addition, it also restored cognitive function as demonstrated SCAG scores and increased vigilance as recorded in the EEG-power spectra. It therefore can be regarded as an analgesic, which has increased potential in the elderly senile or demented patient. Such beneficial effects likely are due to inhibition of monaminergic reuptake rather than an opioid-related effect. Although the present study lacks the comparison of a control placebo group, the present pilot report warrants further assessment of analgesics such as tramadol in the ageing population.
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61 [41] Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 1991;27:7—17. [42] Miranda HF, Pinardi G. Antinociception, tolerance, and physical dependence comparison between morphine and tramadol. Pharmaol Biochem Behav 1998;61:357—60. [43] Barth H, Durra S, Giertz H, Goroll D, Floh` e L. Long-term administration of the centrally acting analgesic tramadol did not induce dependence or tolerance. Pain 1987;4:S231. [44] Vickers MD, O’Flaherty D, Szekely SM, Read M, Yohizumi J. Tramadol: pain relief by an opioid without respiratory depression. Anaesthesia 1992;47:291—6. [45] Houmes RJM, Vorets MA, Verkaalk A, Erdmann W, Lachmann B. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 1992;74:510—4. [46] Freye E, Rosenkranz B, Neruda B. Die obstipierende Wirkung der Opioide Tilidin-N und Tramadol im Vergleich zu Codein. Eine vergleichende Gegen¨ uberstellung zweier Wirkstoffkonzentrationen bei Probanden. Schmerz 1996;10:254—60. [47] Freye E, Latasch L. Effects of tramadol and tilidine/naloxone on oral—caecal transit and pupillary light reflex. Arzneim Forsch/Drug Res 2000;50:24—30. [48] Lai J, Wa SW, Porreca F, Raffa RB. Tramadol, M1 metabolite and enantiomers for cloned human opioid receptors expressed in tranfected HN9.10 neuroblastoma cells. Eur J Pharmacol 1996;346:369—72. [49] Desmeules JA, Piguet V, Collart L, Dayer P. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Phramacol 1996;41:7—12.
The effects of tramadol on pain relief, fast EEG-power spectrum and cognitive function in elderly patients with chronic osteoarthritis (OA) E. Freye a,∗, J.V. Levy b a
Clinic of Vascular Surgery and Renal Transplantation, Heinrich-Heine-University Clinics of D¨ usseldorf, Moorenstrasse, Germany b Department of Pharmacology & Physiology, University of the Pacific, Webster Street, San Francisco, USA Received 9 November 2005 ; received in revised form 8 March 2006; accepted 10 March 2006 Available online 18 May 2006 KEYWORDS Tramadol; Pain; Elderly; Osteoarthritis; Electroencephalogram; Cognitive function testing (SCAG)
Summary Pain and cognitive impairment in the elderly patient with osteoarthritis (OA) often is managed inadequately with common NSAIDs. We therefore evaluated the opioid-like agent tramadol, preportedly also acting as a monaminergic reuptake inhibitor. Patients (75 years ± 7S.D.; 17 female, 2 male) with chronic OA of the knee, elbow, shoulder and hip complaining of acute pain were given two 50 mg/70 kg oral doses of tramadol 30 min apart. Before, during and 2 h after medication, the following parameters were measured: 1. Heart rate (HR) and blood pressure (BP). 2. Visual analogue scaling (VAS) of pain associated with movement. 3. Relative changes in the EEG-power spectra (␦, , ␣, ) to control, over a 60 s period. 4. Cognitive function using the Sandoz Clinical Assessment Geriatric scale (SCAG). Patients experienced a significant (p < 0.01) reduction in VAS assessed pain from 7.8 ± 2.0 to 2.2 ± 0.5. In the EEG, power in ␦ (0.5—3 Hz) dropped from 50 to 35% (p < 0.005), ␣ (8—13 Hz) increased from 12 to 25% (p < 0.001) and  (13—30 Hz) from 23 to 37% (p < 0.001). There was an improvement (p < 0.001) in both severities of depression and cognitive function scoring. There were no significant changes in HR or BP.
∗
Correspondence to: E. Freye, Deichstrasse 3a, 41468 Neuss-Uedesheim, Germany. Tel.: +49 2131 369 4396. E-mail address: [email protected] (E. Freye).
1366-0071/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2006.03.001
56
E. Freye, J.V. Levy In addition to pain relief, tramadol also improved mood, the ability to perform tasks and reversed disability in cognitively impaired elderly. Subsequent to this pilot trial further studies of tramadol in the elderly are warranted. © 2006 Elsevier B.V. All rights reserved.
1. Introduction Pain in the elderly patient with osteoarthritis (OA) is difficult to manage, because of the stoic attitude of patients, and the possible interaction with other agents often taken by the elderly. Acetaminophen and NSAIDs often are considered agents of choice when peripherally mediated pain is present as in osteoarthritis. However, these agents tend to induce gastrointestinal lesions or hepatic disorders, especially when taken over a long period of time [1,2]. When using newer COX-2 inhibitors (e.g. celebrex), which show a reduced incidence in the formation of gastric lesions [3,4], new safety guidelines have to be observed and they should be avoided in high-risk cardiovascular patients. For instance similar to non-selective NSAIDs, they cause sodium retention by inhibiting COX-2, which occasionally can lead to peripheral oedema, increase in blood pressure and congestive heart failure [5,6]. Therefore, patients with renal insufficiency, hypertension or patients treated with an angiotensinconverting enzyme (ACE) inhibitor and patients using angiotensin receptor antagonists, potassiumsparing diuretics or have decreased renal perfusion should not be given an NSAID or COX-2 inhibitor therapy. Potent CNS-acting analgesics such as opioids tend to induce a marked sedation with lethargy or even delirium [7—9] in the elderly. This is either due to a reduced metabolism of the liver or renal insufficiency resulting in higher plasma concentrations of the opioid [10]. Also, opioids interact with antihypertensive agents (e.g. Ca2+ -channel blockers, -blockers, ACE-inhibitors, etc. [11]), which either results in a potentiation of the sedative effect of the opioid or results in an additive effect of the blood pressure lowering agent [12]. Therefore, highly potent agents like transdermal fentanyl, oral oxymorphone and oxycodone are not considered drugs of choice especially when the patient is opioid na¨ıve [13,14]. While cognitively impaired elderly patients tend to under report pain, their discomfort is no less important than those of cognitively intact patients. Consequently, an analgesic drug of choice for elderly patients with OA is one with the lowest sideeffects profile, including lack of impairing cognitive functions. Tramadol [1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclo-hexan-1-ol] an opioid with
intermediate potency is a suitable choice for the elderly because it is characterized by less side-effects, little interaction with other drugs and has negligible abuse potential [16—18], with a wide margin of safety [19]. Since tramadol also acts as a monaminergic reuptake inhibitor [20,21], possible additional sedative or desynchronizing effects on the EEG were evaluated. Special attention was focused on changes of cognition and attention deficiency, symptoms typically seen in the elderly patient.
2. Materials and methods After obtaining written informed consent and, after approval by the local Human Subjects Committee of the University Clinic, 19 patients (mean age 75 years ± 7S.D.; 17 female, 2 male) with chronic OA of the knee, elbow, shoulder and hip were enrolled in the study. They complained of acute pain during movement and insufficient pain relief with NSAIDs. They were given two doses of 50 mg of an oral solution administered 30 min apart while being in a supine position. Titration of two doses of 50 mg was considered important in order to detect side-effects as early as possible and demonstrate a potential dose-related effect on the electroencephalogram. Before the first dose, prior to, and 30 min after the second dose of the drug, the following parameters were measured: 1. Heart rate (HR) and blood pressure (BP) using a non-invasive pressure monitoring device in the upper extremity. 2. Visual analogue scaling (VAS) of dynamic pain using a metric scale between 0 (no pain) and 10 (unbearable pain). Pain was evaluated while patients were asked to move their affected joint as requested by the investigator. 3. Electroencephalographic activity to determine any potential sedative effect of the opioid. Three Ag/AgCl stick-on electrodes positioned at Fp1 -A1 or Fp2 -A2 , with one electrode on position FpZ as reference (ten—twenty system), were used to record the power spectra in the three EEG frequency bands: ␦ (0.5—3 Hz), (3—8 Hz), ␣ (8—13 H7) and  (13—30 Hz), which can be used to demonstrate changes of vigilance induced by a centrally active agent. Original EEG signals
The effects of tramadol on pain relief from a pre-amplifier were entered into an EEGrecorder (Lifescan® , Diatek, San Diego, USA), which analysed the power (V2 ) in the various EEG-power bands. From the EEG recorder, data were entered into a laptop computer (Kaypro® 2000) with a system software which computed the absolute power within the various frequency bands over a time period of 60 s. Results were printed out on a built-in printer with appropriate frequency response features. Specification and operational features were specifically designed for continuous EEG measurement using an automatic electrode impedance check <5 k of 45 db dynamic range. 4. Individual grading of cognitive function was made using the Sandoz Clinical Assessment Geriatric scaling (SCAG). This permitted analysis of various items related to social factors such as vitality, vigilance and cooperation [22]. Evaluation of SCAG using a total of 18 items was considered appropriate to evaluate the cognitive, affective, social and some physical properties using an intensity analogue scale (1, nonexistent; 2, very weak; 3, weak; 4, weak to medium; 5, medium; 6, moderately severe; 7, severe). An independent observer assessed rating. Thus, assessment was obtained for items such as recent memory, depression, anxiety, loss of orientation, quick-temperedness, unstable mood, loss of motivation, irritability, hostility, indifference to environment, unsociability, uncooperative behaviour, personal hygiene, tiredness, loss of appetite and vertigo. These are used as major measures in evaluating the degree of dementia and because SCAG had been shown to be a reliable tool in evaluating presenile and senile dementia [23,24] and especially useful to determine the efficacy of a specific therapy [25]. This assessment tool was also considered a reliable instrument for detecting beneficial and side-effects of tramadol. It was felt that such measurements were of importance in the present population, since the use of an atypical centrally acting analgesics results in further deterioration of vigilance and concentration in the elderly who already may manifest deficiencies in cognition and attention or who already show symptoms of dementia [26]. Since these measurements were obtained before and after tramadol for the same subject, each subject served as their own control. The duration of action of tramadol is around 4—6 h. Following completion of the study, and once the test medication was proven effective, the patient was changed to
57 a slow release formulation of the agent to assure long-term efficacy.
3. Statistical analysis Before starting the study, a priori statistical power analysis was done. This was necessary to calculate the sample size (number to treat), necessary for demonstration of statistical significance in the study. Power analysis demonstrated pragmatic constraints for the investigation. In order to detect the maximum possible sample size, compromised power analysis was performed. Power was calculated using the standard deviations in the different EEG-spectra of a previous study in patients undergoing treatment with tramadol for reversal of migraine pain [27]. Computation of sample size for paired t-test yielded a number 18 subjects necessary for having a 95% power to detect a before—after difference at a significance level (˛) of 0.05 (two-tailed). For computation of relative power changes, each EEG-power spectrum of the control period was set at 100 and the changes at the given endpoints were compared to control. Parameters at different stages after tramadol were compared with the period before the agent using Friedman’s test for repeated measures of analysis of variance of ranks. The two-sided Student—Newman—Keuls test for multiple comparisons was used to calculate significance levels compared to control. In addition, total scoring of all items in SCAG was compared to pre-drug control. A value of p < 0.05 was considered statistically significant. Data are shown as mean value ± standard deviation (S.D.).
4. Results Following two doses of 50 mg/70 kg of tramadol, elderly patients experienced a significant (p < 0.01) reduction in pain of their osteoarthritic joint(s) (Fig. 1). From a mean control VAS of 7.8 (±2.0S.D.), pain intensity dropped to a mean of 2.2 (±0.5S.D.) suggesting a positive analgesic effect of the agent. It should be noted, that a total dose of 100 mg/70 kg and not a single dose of 50 mg/70 kg was needed to produce therapeutic effects. In addition to the reduction in pain, patients demonstrated significant changes in their EEG (Fig. 2). In the electrical cortical activity, power of the ␦-band of the EEG (0.5—3 Hz) dropped from a relative 50 to 35% (p < 0.01), while power in the ␣band (8—13 Hz) increased from a relative 12 to 25% (p < 0.005). Power in the fast frequency -domain
58
Fig. 1 Visual analogue scaling (VAS) 0—10 in elderly patients with osteoarthritic pain before and after tramadol 100 mg/70 kg (mean ± S.D.).
(13—30 Hz) increased from a relative 23 to 37%. This was highly significant (p < 0.001) when compared to the period before tramadol (Fig. 2). The Sandoz Clinical Assessment Geriatric scoring for grading of cognitive function indicated that there was a high score in the intensity of symptoms before tramadol was administered. The high score revealed impairment in cognitive function such as
E. Freye, J.V. Levy
Fig. 2 Grand mean changes of power in EEG spectra ␦ (0.5—3 Hz), (3—7 Hz), ␣ (7—13 Hz) and  (13—30 Hz), before and after incremental doses of tramadol. Note the increase of power in the fast ␣- and -domain.
derangement in thinking, an affective disorder, as well as impairment in vigilance and vitality, all of which attributed to the high global score in cognitive and cerebral dysfunction. On the other hand, items such as loss of independence and personal hygiene had less impact on the global cognitive dysfunction score. While the total score for all items
Fig. 3 Summary of selected items in depression scaling and evaluation of cognitive function, using a polar coordinate system where each data point is specified by a radius from the centre.
The effects of tramadol on pain relief was 80 ± 11 before tramadol, it decreased to a mean of 55 ± 14 after the tramadol. The scores for severity of depression and reduced cognitive function in this elderly patient population revealed a highly significant (p < 0.001) improvement following the agent (Fig. 3). There was no significant increase in heart rate and blood pressure following drug treatment.
5. Discussion Treatment of OA in elderly patients with tramadol produces a sufficient relief of pain. This analgesia is not mediated via a blockade of peripheral nociceptors, which in osteoarthritis are the source of nociceptive afferents. Contrary to acute pain seen with acute stage of inflammation in rheumatoid arthritis, in chronic osteoarthritis pain has sensitized the spinal tract [28]. This explains in part the relative ineffectiveness of peripherally acting analgesics such as NSAIDs. Therefore, pharmacologic treatment of pain associated with OA in the elderly should also consider a centrally acting analgesic [11] a concept, which has emerged in modern pain therapy. While opioids in a young patient population is characterized by a small incidence in sideeffects, in the elderly one has to consider a potential interaction with other agents. This may result in pharmacologically related side-effects, which may account for a 56% incidence of delirium [7,8,29]. Therefore, only agents characterized by a high margin of safety [30] but still being effective in managing the arthritic pain should be considered. In this regard, tramadol seemed a suitable agent because it had been shown to be affective in arthritic pain [31] and at the same time shows less side-effects than other opioids [19]. Because nausea is considered a major side-effect shortly after intake of tramadol [16], special care was taken for its avoidance by letting the patient lie down in a supine position for 1 h. While the beneficial antinociceptive effect can be attributed partly to an opioid action of tramadol, selective monaminergic reuptake inhibition [20,21] has to be considered as another mode of action. This would result in increasing activity of the descending pain-inhibitory afferents [32]. Tramadol therefore demonstrates an antinociceptive effect via two synergistic mechanisms, a feature of advantage in patients suffering from OA pain. The monaminergic reuptake inhibition is also of advantage in reversing dementia symptoms. It is generally accepted that the cause of dementia is the chronic release of the excitatory amino acid glutamate, an ensuing increase of influx of Ca2+ -ions and a reduced release of transmitters
59 from neuronal cells, followed by apoptosis [33]. And since it is recognized that essential neurotransmitter release are involved in normal CNS functions, persons with a variety of cognitive and affective disorders may show deficient levels of dopamine, norepinephrine and acetylcholine. Tramadol seems to reverse such effects, especially since the reduction in neuronal transmitter release is opposed by the monaminergic reuptake mechanism of tramadol resulting in restoration of function in cerebral areas normally depressed or inactive [33]. This assumption is supported by experimental data where tramadol administration resulted in an increased release of monaminergic transmitters such as dopamine, norepinephrine and serotonin in the synaptic cleft [15,34,35]. While dopamine and norepinephrine activity affects arousal and attention, dopamine is also thought to have a role in language function. Thus, dopaminergic agents, as been shown in small studies in selected subjects, were able improve alertness or ‘‘arousal’’, attention, concentration, language skills and memory [27,37]. Given these observations, an agent like tramadol increases the levels of the deficient transmitters or mimics transmitters where these natural neurotransmitters are lacking. In addition, the present data in the EEG-power spectra support such concept since improvement of alertness, arousal or attention, was reflected in an increase of power in the fast -band. Contrary to the common observation that opioids result in an increase in power of the slow ␦- and -domain, tramadol significantly reduced power in the slow ␦-band. Such changes can be interpreted as EEG desynchronisation normally seen with an increase in vigilance and attention [36]. Such tramadol-related desynchronisation was also seen in patients undergoing inhalational anesthesia resulting in lightening of the depth of anesthesia [37,38]. Also, unlike a potent analgesic like alfentanil, tramadol induces a dose-related increase in amplitude height of the somatosensoryevoked potential of the EEG in non-anaesthetized canines [39], all of which underlines a non-opioid activity of the agent. Also, contrary to other opioids of similar potency, tramadol has a low risk of addiction [40—42], development of tolerance after long-term administration [43] and has a low incidence on respiratory depression [44,45]. There is less inhibition of gastrocecal transit time, and it has a reduced miotic effect [46,47]. Such absence of opioid-related effects is explained by opioid receptor binding studies, where affinity of tramadol was 1/1000-fold less than that of morphine [48]. From these data it can be concluded that the analgesic potency of tramadol is related partly due to its opioid binding capacity
60 of the metabolite M1 [15] but mostly due to its monaminergic reuptake mechanism, which affects the descending inhibitory pain pathways [20,49]. The mechanism of this beneficial activation of the descending inhibitory system is the same mechanism that also contributes to a reduction of cognitive dysfunction often observed in the elderly patient population. In summary, the opioid tramadol was able to reduce acute pain in elderly patients with chronic osteoarthritis. In addition, it also restored cognitive function as demonstrated SCAG scores and increased vigilance as recorded in the EEG-power spectra. It therefore can be regarded as an analgesic, which has increased potential in the elderly senile or demented patient. Such beneficial effects likely are due to inhibition of monaminergic reuptake rather than an opioid-related effect. Although the present study lacks the comparison of a control placebo group, the present pilot report warrants further assessment of analgesics such as tramadol in the ageing population.
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