Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain

BACKGROUND AND PURPOSE

Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ-opioid receptor. Buprenorphine and its active metabolite are believed to act through µ-, κ- and δ-receptors and may therefore possess different analgesic and anti-hyperalgesic effects compared with pure µ-receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti-hyperalgesic effects of buprenorphine and fentanyl.

EXPERIMENTAL APPROACH

Twenty-two healthy volunteers were randomized to treatment with transdermal buprenorphine (20 µg·h⁻¹, 144 h), fentanyl (25 µg·h⁻¹, 72 h) or placebo patches in a double-blind, cross-over experimental pain study. The experimental pain tests (phasic pain, sensitization) involved pressure at the tibial bone, cutaneous electrical and thermal stimulation, intramuscular nerve growth factor, UVB light burn injury model and intradermal capsaicin-induced hyperalgesia. Pain testing was carried out at baseline, 24, 48, 72 and 144 h after application of the drugs.

KEY RESULTS

Compared with placebo, buprenorphine, but not fentanyl, significantly attenuated pressure at the tibial bone as well as pressure pain in the primary hyperalgesic area induced by UVB light The two drugs were equipotent and better than placebo against cutaneous thermal pain stimulation), but failed to show significant analgesic effect to cutaneous electrical stimulation, nerve growth factor-induced muscle soreness and to capsaicin-induced hyperalgesia.

CONCLUSIONS AND IMPLICATIONS

Buprenorphine, but not fentanyl, showed analgesic effects against experimentally induced, bone-associated pain and primary hyperalgesia compared with placebo. These tissue- and modality-differentiated properties may reflect the variable effects of opioid drugs observed in individual patients.     

Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol

Previous studies have demonstrated that delta9-tetrahydrocannabinol (THC) enhances the antinociceptive potency of many opioids administered by a variety of different routes of administration. We hypothesized that THC would enhance fentanyl or buprenorphine analgesia via the transdermal route of administration. THC was first demonstrated to enhance opioid antinociception when both drugs were administered parenterally in a hairless guinea pig model using the pin prick test. A low dose of THC (50 mg/kg, i.p.) produced no antinociception. However, THC enhanced the potency of s.c. fentanyl by 6.7-fold, and s.c. buprenorphine in a non-parallel fashion. For the transdermal studies, THC, fentanyl or buprenorphine was applied by pipette to the skin of the dorsum between the fore- and hind-flanks and covered with individual Tegederm patches. THC (400 mg/kg) produced no antinociception. However, THC enhanced fentanyl's potency by 3.7-fold at 2-h, and 5.8-fold at 4-h. Buprenophine's potency was increased 8.2-fold at 2-h and 7.2-fold at 4-h when co-administered with THC. These results indicate that the enhancement of transdermal opioids by THC could lead to the design of an effective combination analgesic patch.     

Pharmacokinetics of transdermal buprenorphine patch in the elderly

Purpose

Transdermal buprenorphine patches provide comparable pain relief to that of low-potency opioids in elderly individuals. However, specific data on their use in elderly individuals is limited. This study investigated and compared the PK of buprenorphine transdermal patches in elderly (≥75 years) versus younger (50–60 years) individuals.

Methods

This was a multiple-dose, open-label, parallel-group study in healthy volunteers split into two age groups (younger, 50–60 years; elderly, ≥75 years) with 37 individuals in each. Study participants received two consecutive 7-day buprenorphine 5 μg/h transdermal patch applications, and blood samples were collected on the week of the second patch application [day 7 (predose), days 8, 9, 10, 12, and 14] to determine PK at steady state. Pharmacokinetic parameters were determined for buprenorphine and norbuprenorphine. Safety was assessed by analyzing adverse events, hematology, clinical chemistry, urine analysis, vital signs, electrocardiogram (ECG), and physical examinations.

Results

The area under the plasma concentration-time curve at steady state (AUC_tau), measured over one dosing interval, was similar for elderly [mean ± standard deviation (SD) 9,940 pg/h/ml (4,827 pg/h/ml] and younger [mean ± SD 11,309 (3,670 pg/h/ml] individuals. Bioequivalence was not demonstrated between groups, which may be attributable to the relatively high level of variability in individual plasma profiles. More adverse events were reported by younger (216) than elderly (164) study participants.

Conclusions

No dosage alterations are necessary for PK reasons when treating elderly people with buprenorphine transdermal patches.     

Use of transdermal fentanyl without prior opioid stabilization in patients with cancer pain

OBJECTIVE: To determine the safety and efficacy of transdermal fentanyl for pain relief in cancer patients and to compare the effects on patients according to whether they had previously received strong opioids, weak opioids or non-opioid analgesia. METHODS: Cancer patients requiring strong analgesia were recruited into an open-label, multicentre study, conducted in eight countries. Patients received transdermal fentanyl treatment for 28 days. Pain severity, overall satisfaction with pain control, convenience of use of patches and treatment preferences were recorded daily. RESULTS: Of the 292 participants, 135 had previously received a strong opioid, 84 had previously received a weak opioid and 73 had received no regular opioids. Thirty-eight patients did not complete the study, mainly due to adverse events. For all groups the proportion of patients with 'good to excellent' pain control increased after transdermal fentanyl treatment. Transdermal fentanyl was well tolerated, with the most common treatment-related adverse events being nausea, vomiting and constipation. The percentage of strong-opioid-tolerant patients with constipation decreased following transdermal fentanyl treatment and increased slightly in the strong-opioid-na?ve groups. Most patients rated the convenience of the patches as 'good to excellent', and most preferred transdermal fentanyl to their previous therapy. CONCLUSIONS: Transdermal fentanyl is an effective and well-tolerated treatment for cancer-related pain for patients regardless of whether they have previously received opioids. Previous guidelines have often advocated initial dose finding with short-acting opioids but this study demonstrates that such a complex titration and conversion schedule may not be necessary,and that treatment may be initiated directly with long-acting formulations such as transdermal fentanyl when previous analgesic therapy fails to provide adequate relief.     

Buprenorphine 5, 10 and 20 μg/h transdermal patch: a guide to its use in chronic non-malignant pain

Buprenorphine lower-dose (5, 10 and 20?μg/h) transdermal patches, which are administered once every 7 days, are indicated in the management of chronic non-malignant pain. This review focuses on the labelling of this formulation (BuTrans?) in the EU. The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip and/or knee has been demonstrated to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol and generally superior to a matching transdermal placebo patch. When used together with regularly scheduled oral paracetamol (acetaminophen), transdermal buprenorphine was noninferior to codeine plus paracetamol. Transdermal buprenorphine has also shown analgesic efficacy in patients with chronic non-malignant pain of various causes.     

Transdermal buprenorphine

Buprenorphine is a low molecular weight, lipophilic, opioid analgesic. Recently, a transdermal matrix patch formulation of buprenorphine has become available in three dosage strengths designed to release buprenorphine at 35, 52.5 and 70 micro g/h over a 72-hour period. At least satisfactory analgesia with minimal requirement for rescue medication (50% of patients treated with transdermal buprenorphine, in two trials. Furthermore, despite the availability of rescue medication to all patients, those receiving transdermal buprenorphine tended to experience greater pain relief, reduced pain intensity and longer pain-free sleep. Transdermal buprenorphine was generally well tolerated. Systemic adverse events were typical of opioid treatment or were attributable to the underlying disease.     

Use of transdermal fentanyl without prior opioid stabilization in patients with cancer pain

SUMMARY

Objective: To determine the safety and efficacy of transdermal fentanyl for pain relief in cancer patients and to compare the effects on patients according to whether they had previously received strong opioids, weak opioids or non-opioid analgesia.

Methods: Cancer patients requiring strong analgesia were recruited into an open-label, multicentre study, conducted in eight countries. Patients received transdermal fentanyl treatment for 28days. Pain severity, overall satisfaction with pain control, convenience of use of patches and treatment preferences were recorded daily.

Results: Of the 292 participants, 135 had previously received a strong opioid, 84 had previously received a weak opioid and 73 had received no regular opioids. Thirty-eight patients did not complete the study, mainly due to adverse events. For all groups the proportion of patients with ‘good to excellent’ pain control increased after transdermal fentanyl treatment. Transdermal fentanyl was well tolerated, with the most common treatment-related adverse events being nausea, vomiting and constipation. The percentage of strong-opioid-tolerant patients with constipation decreased following transdermal fentanyl treatment and increased slightly in the strong-opioid-naïve groups. Most patients rated the convenience of the patches as ‘good to excellent’, and most preferred transdermal fentanyl to their previous therapy.

Conclusions: Transdermal fentanyl is an effective and well-tolerated treatment for cancer-related pain for patients regardless of whether they have previously received opioids. Previous guidelines have often advocated initial dose finding with short-acting opioids but this study demonstrates that such a complex titration and conversion schedule may not be necessary, and that treatment may be initiated directly with long-acting formulations such as transdermal fentanyl when previous analgesic therapy fails to provide adequate relief.     

Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl

Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same adverse effects as other opioids, mainly sedation, nausea, vomiting and constipation. In comparison with oral morphine, TTS fentanyl causes fewer gastrointestinal adverse events. The risk of hypoventilation is comparatively low in cancer patients. Sufentanil and buprenorphine may also be suitable for transdermal delivery, but clinical results are not yet available. Transdermal morphine is only useful if applied to de-epithelialised skin. However, iontophoresis may allow transdermal administration of opioids, including morphine, with a rapid achievement of steady state concentrations and the ability to adjust delivery rates. This would be beneficial for acute and/or breakthrough pain, and initial clinical trials are in progress.     

Transdermal buprenorphine in chronic pain: indications and clinical experience

Transdermal buprenorphine has been shown to be effective in managing moderate-to-severe cancer pain and severe pain that is unresponsive to nonopioid analgesics. In clinical trials, it provided better pain relief than placebo, despite a higher consumption of rescue analgesia by placebo patients. Analgesia was rated as satisfactory or better by 90% of patients in a long-term follow-up study and 94.6% considered the buprenorphine matrix patch to be user friendly. Transdermal buprenorphine is well tolerated; most adverse events are transient local reactions to the patch or systemic effects typical of treatment with opioids. Even in opioid-experienced volunteers, buprenorphine does not cause respiratory depression at doses up to 70-times higher than those used for analgesia. No problems have been encountered when switching from another opioid to transdermal buprenorphine, or in combining the buprenorphine patch with intravenous morphine or tramadol for breakthrough pain. There is a growing body of evidence that transdermal buprenorphine may be particularly useful for managing neuropathic pain. Most notably, it appears to be effective in treating hyperalgesic states and syndromes characterized by pronounced central sensitization.     

Buprenorphine 5, 10 and 20 μg/h transdermal patch: a review of its use in the management of chronic non-malignant pain

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of the 7-day lower-dose (5, 10 and 20?μg/h) buprenorphine transdermal patch (BuTrans?, Norspan?) in the management of chronic non-malignant pain, with a focus on European labelling for the drug. Buprenorphine is a semi-synthetic opioid analgesic that acts primarily as a partial agonist at the mu opioid receptor. The transdermal formulation provides continuous delivery of buprenorphine, resulting in relatively consistent plasma drug concentrations throughout the 7-day dosing interval. The analgesic efficacy of transdermal buprenorphine in patients with osteoarthritis of the hip and/or knee has been demonstrated in several randomized controlled trials, which have shown the formulation to be equivalent to sublingual buprenorphine, noninferior to prolonged-release tramadol tablets, noninferior to codeine plus paracetamol (acetaminophen) combination tablets (when transdermal buprenorphine was used together with regularly scheduled oral paracetamol) and generally superior to a matching transdermal placebo patch. Transdermal buprenorphine was significantly more effective than placebo in reducing chronic low back pain of at least moderate severity in two randomized, double-blind, crossover trials. Other clinical trials, including a randomized, double-blind, maintenance-of-analgesia study, have also demonstrated the analgesic efficacy of transdermal buprenorphine in patients with chronic non-malignant pain of various causes. In general, serious adverse events with transdermal buprenorphine are similar to those for other opioid analgesics. Transdermal buprenorphine has a ceiling effect for respiratory depression, and the main risk is when it is combined with other CNS depressants. The most frequently reported adverse events with transdermal buprenorphine are headache, dizziness, somnolence, constipation, dry mouth, nausea, vomiting, pruritus, erythema, application site pruritus and application site reactions. Transdermal buprenorphine was better tolerated than sublingual buprenorphine in a 7-week, randomized, double-blind trial in patients with osteoarthritis pain. Nevertheless, as with other opioids, persistence with transdermal buprenorphine therapy is difficult for many patients because of adverse events or other reasons. Thus, transdermal buprenorphine has generally demonstrated good efficacy and tolerability in clinical trials in chronic non-malignant pain, providing effective background analgesia as part of pain management strategies for patients with osteoarthritis, low back pain and other persistent pain syndromes of at least moderate severity. It also has favourable pharmacodynamic and pharmacokinetic properties, which have beneficial clinical implications, most notably the convenience of once-weekly administration and no need for dosage adjustments in the elderly or those with compromised renal function, making it an opioid of choice in these patients, and a useful therapeutic option overall in the management of chronic non-malignant pain.     

A novel approach to pharmaco-EEG for investigating analgesics: assessment of spectral indices in single-sweep evoked brain potentials

Aims

To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl.

Methods

Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps.

Results

Visual inspection revealed no difference between active treatments and placebo (all P > 0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12–32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P < 0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90).

Conclusion

In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.     

A study of transdermal fentanyl in cancer pain at Aichi-Cancer Center

In Japan, transdermal fentanyl (Durotep Patch) was launched in March 2002, and it was regarded as making opioid rotation possible. When changing from morphine to transdermal fentanyl, the efficacy ratio of 1:150 is used in Japan as well as in many other countries. However, the ratio of 1:100 is used in Germany. As a result, a dose increase in transdermal fentanyl is often required to control pain. We studied transdermal fentanyl use in the Aichi Cancer Center (ACC) to investigate the actual conversion ratio and appropriate switching by following up 144 patients (81 men, 63 women) who had received transdermal fentanyl in the ACC from March 19, 2002, to April 30, 2003. Transdermal fentanyl improved pain control in patients who had difficulty in tolerating oral medication or in continuing morphine because of side effects. Regression analysis indicated that the efficacy ratio of oral morphine to transdermal fentanyl was 1:78. As the fentanyl dosage was excessive even in some patients who followed the recommended morphine/fentanyl conversion of 150:1, it is dangerous to use the conversion ratio of 78:1 at first. Morphine side effects were reduced in some patients who changed to transdermal fentanyl, but there was no reduction in those who needed high-dose morphine for rescue analgesia. Therefore it is safe and effective to use low-dose transdermal fentanyl in the beginning and to control pain promptly using rescue morphine based on the present recommended dosage. For opioid rotation, quick-acting opioids other than morphine are expected to be launched in Japan.     

Pharmacodynamic Modelling of Placebo and Buprenorphine Effects on Event‐Related Potentials in Experimental Pain

The purpose of the study was to investigate placebo and buprenorphine effects on event‐related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Nineteen healthy volunteers received transdermal placebo and buprenorphine in a cross‐over study. Drug plasma concentrations and ERPs after electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hrs after administration. Placebo and concentration‐effect models were fitted to data using non‐linear mixed‐effects modelling implemented in NONMEM (V7.2.0.). Pharmacodynamic models were developed to adequately describe both placebo and buprenorphine ERP data. Models predicted significant placebo effects, but did not predict significant effects related to buprenorphine concentration. Models revealed that ERPs varied both between subjects and between study occasions. ERPs were found to be reproducible within subjects and occasions as population variance was found to be eight times higher than the unexplained variances. Between‐subject variance accounted for more than 75% of the population variance. In conclusion, pharmacodynamic modelling was successfully implemented to allow for placebo and variability correction in ERP of experimental pain. Improved outcome of ERP studies can be expected if variation between subjects and study occasions can be identified and described.     

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5–2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra‐operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and post‐operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.     

Iontophoretic drug delivery system: focus on fentanyl

Fentanyl iontophoretic transdermal system (ITS) is a novel, patient-activated drug delivery device used for the management of acute postoperative pain in the hospital setting. This credit-card-sized device uses an imperceptible current of 170 milliampere to actively deliver a fentanyl hydrochloride 40-microg dose into the vasculature over a 10-minute interval. The unit is programmed to lock out further doses after either 80 doses or 24 hours, whichever is reached first. When comparing fentanyl ITS with intravenously administered fentanyl, serum concentrations differ significantly at 10 minutes after the initial dose is administered: 0.1 ng/ml for fentanyl ITS versus 0.7 ng/ml for intravenous fentanyl. Fentanyl ITS absorption increases in a time-dependent fashion over the first 10 hours of dosing. Other pharmacokinetic parameters of fentanyl ITS are comparable to those of intravenous fentanyl after 24 hours (maximum concentration 1.37 and 1.82 microg/ml, time to maximum concentration 0.65 and 0.58 hr, and area under the concentration-time curve at 23-24 hrs 1.23 and 1.34 microg x hr/ml for fentanyl ITS and intravenous fentanyl, respectively,). This new technology exhibited superior analgesia compared with placebo in two placebo-controlled studies that used time to exit as a primary end point. In addition, fentanyl ITS proved equivalent to patient-controlled analgesia with intravenous morphine. Although adverse effects were congruent with those expected from pure-agonist opioids, subjects assigned to the ITS group did experience a higher rate of mild, clinically nonsignificant erythema at the system placement site. Judicious monitoring for opioid-induced respiratory depression is recommended for fentanyl ITS, although this adverse effect has not been observed in clinical trials. Fentanyl ITS may provide another useful alternative in the management of acute postoperative pain.     

芬太尼透皮贴剂不同治疗方案在癌痛治疗中的疗效观察

目的:评价芬太尼透皮贴剂不同治疗方案的镇痛效果与不良反应(ADR)。方法:将189例癌痛患者随机分为3组:芬太尼透皮贴剂常规剂量组(A组)、芬太尼透皮贴剂常规剂量+12h吗啡控释片组(B组)、2倍常规剂量芬太尼透皮贴剂+12h吗啡控释片组(C组),治疗6d后采用视觉模拟量表(VAS)疼痛评分比较3组的疗效。结果:A组与B、C组疗效比较有显著性差异(P<0.05或P<0.01),C组与B组治疗效果也有差异性(P<0.05),3组ADR比较无显著性差异(P>0.05)。结论:与A、B组比较,C组治疗方案发挥良好的镇痛效果,安全性高,有较高的临床应用价值。     

芬太尼透皮贴剂治疗中重度癌性疼痛的临床观察

目的:观察芬太尼透皮贴剂对中晚期癌症镇痛的效果。方法:对120例具有中重度癌痛患者进行治疗。初治病人最初剂量为25μg·h-1;对以前曾用过强阿片类药物的患者根据病人用药情况进行芬太尼透皮贴剂剂量转换。结果:本组患者总缓解率95.0%(114/120),其中完全缓解率为80.0%(96/120),中度和明显缓解率为15.0%(18/120)。结论:芬太尼透皮贴剂治疗中重度癌性疼痛疗效确切,可作为口服强阿片类药物外的替代治疗,现已应用于临床。     

Treatment of chronic pain in older people: evidence-based choice of strong-acting opioids

In the treatment of chronic malignant and non-malignant pain, opioids are used as strong analgesics. Frail elderly patients often have multiple co-morbidities and use multiple medicines, leading to an increased risk of clinically relevant drug-drug and drug-disease interactions. Age-related changes and increased frailty may lead to a less predictable drug response, increased drug sensitivity, and potential harmful drug effects. As a result, physicians face a complex task in prescribing medication to elderly patients. In this review, the appropriateness of the strong-acting opioids buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol is determined for use in elderly patients. Evidence-based recommendations for prescribing strong opioids to the frail elderly are presented. A literature search was performed for all individual drugs, using a validated and published set of 23 criteria concerning effectiveness, safety, pharmacokinetics and pharmacodynamics, experience, and convenience in elderly patients. First, information on the criteria was obtained from pharmaceutical reference books and a MEDLINE search. The information obtained on the individual drugs in the class of opioids was compared with the reference drug morphine. Evidence-based recommendations were formulated on the basis of the pros and cons for the frail elderly. Using the set of 23 criteria, no differentiation can be made between the appropriateness of buprenorphine, fentanyl, hydromorphone, morphine and oxycodone for use in elderly patients. Methadone has strong negative considerations in the treatment of chronic pain in the frail elderly. Methadone has a high drug-drug interaction potential and is associated with prolongation of the QT interval and a potential risk of accumulation due to a long elimination half-life. In addition, methadone is difficult to titrate because of its large inter-individual variability in pharmacokinetics, particularly in the frail elderly. Because of a lack of empiric knowledge, the use of tapentadol is not recommended in frail elderly persons. Nevertheless, tapentadol may prove to be a useful analgesic for the treatment of chronic pain in frail elderly persons because of its possible better gastrointestinal tolerability. In the treatment of chronic pain in the frail elderly, the opioids of first choice are buprenorphine, fentanyl, hydromorphone, morphine and oxycodone. In order to improve the convenience for elderly patients, the controlled-release oral dosage forms and transdermal formulations are preferred.     

The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus

ABSTRACT

Background: The semi-synthetic opioid, buprenorphine, has the general structure of morphine but differs from it in significant ways, both pharmacologically and clinically. A number of long-term studies have shown effective, long-lasting analgesia in moderate to severe cancer and non-cancer pain, including neuropathic pain, with a low incidence of constipation, nausea, dizziness and tiredness. The treatment of moderate to severe chronic pain has improved as a result of the development of new methods of administration of this substance, particularly the introduction of the transdermal drug delivery system, which offers a number of advantages over the usual oral and parenteral routes.

Scope: A panel of experts specialising in palliative care and pain treatment was convened in November 2007 to discuss their clinical experiences with transdermal buprenorphine and other analgesics. The aim was to provide practical guidance on the treatment of cancer pain with transdermal buprenorphine, particularly when there is a need for increasing pain relief leading to high and increasing doses. A literature search on the use of transdermal buprenorphine was carried out for the panel meeting (based on a search of PubMed to November 2007 – since updated by an additional search for the period to February 2009) and a number of case histories were presented and discussed. This commentary article presents this evidence and the consensus findings of the expert panel.

Findings: The Panel reached consensus that transdermal buprenorphine was a valuable treatment for chronic cancer pain, including its neuropathic components. A number of general recommendations were made. Large-scale, randomised clinical studies are needed to provide product comparisons on the use of analgesics in the treatment of neuropathic pain although it was recognised that such studies may not be practicable. Data on the treatment of acute and chronic pain should be kept separate in general. Physicians should be made more aware of the problem of hyperalgesic effects of some opioids in long term use. Buprenorphine in contrast has been described to exert an antihyperalgesic effect. The development of analgesic tolerance with some opioids in long term use and the lack of it with buprenorphine requires further studies. The registered dose range of 35–140?µg/h was considered adequate to achieve sufficient pain relief in most patients although some members of the panel presented data showing that increases beyond this dose range provided improved pain relief if slow titration is used. However, it was generally felt that more evidence was needed before this could become generally acceptable.

Conclusion: The consensus was that transdermal buprenorphine has a valuable role to play in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function.     

Dermal penetration of fentanyl: inter- and intraindividual variations

Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra- and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21-105 ng/cm2/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter-individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate-determining factor for the other individuals included in this study.