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5-1 芬太尼癌症镇痛

Clinical note

Transdermal fentanyl in cachectic cancer patients

Tarja Heiskanen a,*,Sorjo M?tzke b ,Soile Haakana a ,Merja Gergov c ,Erkki Vuori c ,Eija Kalso a,d

Pain Clinic,Department of Anesthesiology and Intensive Care Medicine,Helsinki University Central Hospital,P.O.Box 140,00029HUS Helsinki,Finland b

Department of Clinical Physiology,Jorvi Hospital,Espoo,Finland c

Department of Forensic Medicine,University of Helsinki,Helsinki,Finland d

Institute of Clinical Medicine,University of Helsinki,Helsinki,Finland

a r t i c l e i n f o Article history:

Received 30January 2009

Received in revised form 9April 2009Accepted 14April 2009

Keywords:

Transdermal fentanyl Absorption Cachexia Cancer pain Opioid

a b s t r a c t

Fentanyl is an opioid with high lipid solubility,suitable for intravenous,spinal,transmucosal and trans-dermal administration.The transdermal fentanyl patch has become widely used in the treatment of both malignant and non-malignant chronic pain.The absorption of fentanyl from the patch is governed by the surface area of the patch,by skin permeability and by local blood ?ow.The aim of this study is to ?nd out whether absorption of fentanyl in cachectic patients with cancer-related pain is different from that of normal weight cancer patients.We recruited ten normal weight (mean body mass index (BMI)23kg/m 2)and ten cachectic (mean BMI 16kg/m 2)cancer pain patients.A transdermal fentanyl patch with a dose approximately equianalgesic to the patients’previous opioid dose was administered to the upper arm of the patient for 3days.Prior to patch application,the height,weight and BMI of the patient,as well as upper arm skin temperature,local sweating,thickness of skin fold and local blood ?ow were mea-sured.Plasma fentanyl concentrations were analyzed from blood samples taken at baseline,4,24,48and 72h.Plasma fentanyl concentrations adjusted to dose were signi?cantly lower at 48and 72h in cachectic patients than normal weight patients.The cachectic patients had a signi?cantly thinner upper arm skin fold,but no differences were found in local blood ?ow,sweating,or skin temperature.Absorp-tion of transdermal fentanyl is impaired in cachectic patients compared with that of normal weight can-cer pain patients.

1.Introduction

Fentanyl is a synthetic l -opioid receptor agonist used in the treatment of acute peri-and postoperative pain both intravenously and spinally.The high lipid solubility and low molecular weight of fentanyl make it suitable even for oral transmucosal and transder-mal administration.Transdermal fentanyl has shown to provide effective,continuous pain relief in chronic cancer-related pain [1,11,16]and chronic non-malignant pain [2,5].

Transdermal fentanyl patches are available as transdermal ther-apeutic systems with a drug reservoir and a rate control membrane controlling fentanyl ?ux to the skin,or as matrix systems where fentanyl is dissolved in a polyacrylate adhesive.These two systems have comparable ef?cacy and safety [8].

The absorption of fentanyl from a transdermal therapeutic sys-tem is proportionate to the surface area of the patch.The anatom-ical site of application (chest,abdomen and thigh)of the patch does not have a clinically signi?cant effect on fentanyl absorption [18].After placement of a fentanyl patch,serum fentanyl concen-trations gradually increase during the ?rst 14h and stay relatively

constant from 14to 24h [25].The increase in plasma fentanyl con-centration is slower in elderly people [24].With continuous appli-cation of patches,steady state fentanyl concentrations are approximated by the second dose [19].A cutaneous depot of fenta-nyl is created in the upper layers of the skin,the stratum corneum,covered by the fentanyl patch;when the patch is removed,absorp-tion of fentanyl continues from this site [9].From the stratum cor-neum,fentanyl is passively diffused to the dermis,where the drug is removed by the cutaneous microcirculation.

Absorption of fentanyl from the patch is governed by skin per-meability and by local blood ?ow.Because permeation of fentanyl through the skin is a much slower process than its removal by the cutaneous blood ?ow,only extreme variations in blood supply should in?uence fentanyl absorption [10].Heat has been shown to increase the rate of fentanyl absorption by up to 30%[3].In a re-cent study in cancer patients,great variations in the fraction of fen-tanyl absorbed from the patch were observed,from 18%to 100%[23].The mean body mass index (BMI)of these patients was within the normal range (22kg/m 2);no correlation between BMI and bio-availability was seen,but BMI was correlated to the total fentanyl clearance.

In clinical practice,cachectic cancer patients often seem to re-quire higher transdermal fentanyl doses for adequate analgesia

*Corresponding author.Tel.:+358504272386;fax:+358947175641.E-mail address:tarja.heiskanen@hus.?(T.Heiskanen).w w w.e l s e v i e r.c o m /l o c a t e /p a i n

PAIN ò144(2009)218–222

than normal weight or obese cancer patients,without suffering from intolerable opioid adverse effects.Studies on the effect of ca-chexia on the pharmacokinetics and pharmacodynamics of trans-dermal fentanyl or any other drug have not been published.Our study hypothesis was that cachexia would have an effect on skin permeability,thereby reducing fentanyl absorption.The purpose of this study was to analyze the pharmacokinetic characteristics of transdermal fentanyl in cachectic and normal weight cancer pa-tients with pain.

2.Methods

The study was prospective.Twenty adult(18–75years)Finnish speaking patients with cancer-related pain were recruited:ten normal weight(BMI20–25kg/m2)and ten cachectic (BMI<18kg/m2)patients.Patients with chronic(at least1month) cancer-related pain requiring treatment with WHO step3opioid analgesics were included.Exclusion criteria were:impaired cogni-tive function,fever,pregnancy and lactation,clinically signi?cant renal,hepatic or cardiac insuf?ciency,skin disease precluding use of fentanyl patch,and use of potent CYP3A4inhibiting drugs(e.g. erythromycin,diltiazem,?uoxetine,?uvoxamine,verapamil).The study was approved by the institutional ethics committee of the Helsinki University Central Hospital and the Finnish National Agency of Medicines.The patients were given verbal and written information on the study,and they were asked to sign a written in-formed consent.

At the?rst visit to the Pain Clinic,the height(m),weight (kg)and body mass index(BMI)(weight(kg):height2(m2))of the patients were recorded.Before fentanyl patch application to either upper arm,thickness of an upper arm skin fold(Base-lineòSkinfold Caliper,Fabrication Enterprises,Inc.,USA),local skin blood?ow[7](ABB MetrawattòLaser Doppler Flowmeter, ABB,Sweden),skin temperature(Tempettò,SENSELab,Sweden), and transepidermal water loss as a measure of local sweating (Del?nòVapoMeter,Del?n Technologies,Finland)were measured.

The location and intensity of pain(visual analogue scale,VAS; 0–100mm)were recorded at baseline and immediately prior to each blood sample.The patients then continued recording the intensity of pain and the incidence and duration of possible ad-verse events,including skin irritation,in a diary twice daily throughout the study.The outpatients visited the Pain Clinic daily until Day4,or the study nurse collected the blood samples from the patients at home.The inpatients were visited on the hospital wards.

A transdermal fentanyl patch(Durogesicò,Janssen-Cilag Oy, Finland)was applied to the skin of either upper arm on Day 1.The last dose of the former opioid was ingested simulta-neously.In this study,fentanyl dose was calculated by?rst converting the former daily opioid dose to oral morphine using the ratio2:3(oxycodone:morphine)[14]and then,using the ratio100:1(morphine:fentanyl)[6],further to an approxi-mately equianalgesic dose of transdermal fentanyl.The dose of transdermal fentanyl was not increased during the study (3days).Adverse effects were treated as needed(https://www.wendangku.net/doc/c86680000.html,xatives for constipation,haloperidol for nausea).Breakthrough pain was treated as needed using oral immediate-release oxycodone solution(Helsinki University Hospital Pharmacy,Helsinki, Finland).

Blood samples,10ml each,for determination of plasma fenta-nyl concentration were drawn at baseline immediately before the ?rst patch application,and at4,24,48and72h(±1h).The samples were drawn into EDTA tubes,centrifuged at3000rpm for10min and frozen to await analysis.2.1.Fentanyl assay

In the liquid chromatography–mass spectrometry method sam-ples were extracted with butyl acetate at pH7.The extracts were run by Agilent LC1100binary pump system(Agilent Technologies, Waldbronn,Germany)on a Genesis C18reversed phase column (Phenomenex,Torrance,CA,USA).The mass spectrometric analysis was performed with an AB/MDS Sciex3200QTrap LC–MS/MS instrument(Applied Biosystems,Concord,ON,Canada)using mul-tiple reaction monitoring.The collision energy and declustering potential was30eV and40V,respectively.The monitored transi-tions were m/z337/188and m/z337/105for fentanyl,and m/z 342/188for fentanyl-d5.Quantitation was based on a6-point cal-ibration from0.2to200l g/L using fentanyl-d5as an internal stan-dard.The limit of quantitation for the method was0.1l g/L.

For comparison of the plasma fentanyl concentrations between the study groups,the concentrations were adjusted to the fentanyl dose by dividing the actual plasma concentration at each time point by the patient’s dose.Statistical analysis was performed using two-way repeated measures analysis of variance followed by the independent samples t-test(adjusted plasma concentra-tions)or using the independent samples t-test alone(fentanyl dose,skin characteristics).Signi?cance was set at p<0.05.

3.Results

Ten normal weight(mean BMI23kg/m2)and ten cachectic (mean BMI16kg/m2)patients completed the study(Table1).Time since cancer diagnosis in all patients ranged from2weeks to 14years,the median time being shorter in the normal weight pa-tients than in the cachectic patients(2.5months versus 5.5months,respectively).

Four more patients completed the study but were excluded from further analysis because of accidental loosening of the patch during the?rst study day(one patient),changing the patch on Day 2by an uninformed ward nurse(one patient),and remarkable low-er body oedema increasing the body mass index of the otherwise cachectic patients(two patients)(Fig.1).

The mean(±SEM)daily transdermal fentanyl dose,approxi-mately equianalgesic to the patient’s previous opioid dose,was sig-ni?cantly higher(p<0.01)in the cachectic patients than in the normal weight patients(96±29l g/h versus43±10l g/h,respec-tively)(Table2).

When adjusted to dose,the plasma fentanyl concentrations at 48and72h were signi?cantly lower in the cachectic patients than in the normal weight patients(Fig.2;Table4).The difference at4 and24h was not signi?cant.The maximum unadjusted plasma fentanyl concentrations reached during the study ranged from

Table1

Demographics.

Normal weight Cachectic

Age(years)64±1.962±2.6 Gender(M/F)4/65/5

Cancer type

Pancreas or biliary tract51

Lung or pleura33 Oropharynx or oesophagus13

other1 5.5 Median duration of disease(months) 2.5 5.5 Height(cm)166±3.2172±3.4 Weight(kg)63±4.049±2.8 Body mass index(kg/m2)23±0.616±0.4

Data presented as mean±SEM,except for duration of disease as median.M,male;F, female.

T.Heiskanen et al./PAINò144(2009)218–222219

0.2to 5.4l g/L.The maximum plasma fentanyl concentrations were observed at 24h (median)in all normal weight patients and in the cachectic patients who had previously been using fenta-nyl;the median time to the maximum concentration in the fenta-nyl na?ve cachectic patients was 48h.None of the 12patients who switched from oxycodone or morphine to fentanyl had measurable plasma fentanyl concentrations at 0h,and the 0h fentanyl concen-tration was below the limit of quanti?cation also in two of the eight previous fentanyl users.There were no signi?cant differences between the cachectic and normal weight patients in local skin blood ?ow,skin temperature or local sweating,but the cachectic patients had a signi?cantly thinner upper arm skin fold (p <0.01)(Table 3).

Pain intensity reported by the patients was similar in both groups at baseline and at the end of the study (Table 2).The pain intensity VAS scores did not change signi?cantly during the study period.Seven patients in the normal weight group and ?ve patients in the cachectic group reported opioid-related adverse effects,most commonly nausea or vomiting and headache.The adverse ef-fects were mild and did not require treatment.No skin irritation around the fentanyl patch was reported by the patients or ob-served by the study personnel.4.Discussion

Our results are in agreement with the clinical hypothesis of im-paired transdermal fentanyl absorption in patients with cancer-re-lated cachexia.To our knowledge,transdermal fentanyl absorption in cachectic cancer patients has not been assessed previously,although large interindividual variation in the pharmacokinetic parameters of transdermal fentanyl in cancer patients in general has been reported [11,23].No studies on the effect of cachexia on the absorption of any other transdermal drug have been pub-lished,either.

Cancer cachexia is a syndrome with multifactorial etiology:bio-logical mechanisms that lead to anorexia,inability to eat and tissue wasting include chronic in?ammation and hypercatabolism [4].These alterations may affect skin permeability and contribute to the poor absorption of fentanyl through the cachectic skin.Xerosis,one of the most common cutaneous manifestations in cachectic pa-tients with anorexia nervosa [13],may be an important factor in?uencing transdermal drug absorption in cancer patients as well.In general,absorption of fentanyl from the patch is governed by skin permeability and by local blood ?ow [10].The amount of sub-

Table 3

Application site characteristics at baseline.

Normal weight

Cachectic Thickness of skin fold,mm 4.3±0.7 2.0±0.3*Skin temperature,°C 31.7±0.432.8±0.4Sweating,g/m 2h

8.4±0.98.4±1.6Blood ?ow,perfusion units

32.1±2.7

32.6±2.5

Data presented as mean ±SEM.*

p <0.01.

Fig. 2.Dose-adjusted plasma fentanyl concentrations in normal weight (?lled circles)and cachectic (open squares)cancer pain patients during the 3-day treatment with transdermal fentanyl.Mean values ±SEM are given.*p <0.05.

Table 2

Opioid dose and pain intensity.

Normal weight

Cachectic Previous opioid Fentanyl 53Morphine –1Oxycodone

Transdermal fentanyl dose,l g/h 42±1096±29Pain intensity,VAS 0–100mm At baseline 29±734±8At 72h

35±8

31±8

Data presented as mean ±SEM.VAS,visual analogue scale.

Table 4

Dose-adjusted plasma fentanyl concentrations,l g/L/dose.Time (h)Normal weight Cachectic 00.006(0–0.016)0.008(0–0.016)40.007(0–0.016)

0.008(0–0.016)

240.023(0.016–0.029)0.016(0.008–0.023)480.023(0.016–0.028)0.014(0.008–0.020)72

0.024

(0.013–0.036)

0.012

(0.008–0.015)

Data presented as mean (95%CI).

220

T.Heiskanen et al./PAIN ò144(2009)218–222

cutaneous adipose tissue does not affect transdermal fentanyl absorption.Cutaneous permeation of drugs is primarily mediated by diffusion,and the outer layer of the skin,the keratinous stratum corneum,acts as a lipophilic barrier controlling the rate of absorp-tion[12].In an in vitro diffusion study[21]using cadaver skin,nei-ther sex nor age of the donor of the skin in?uenced fentanyl absorption.However,age seems to cause a delay both in the esca-lation of plasma fentanyl concentrations after patch application and in the elimination half-life of fentanyl[24].In the present study,all patients were elderly and the mean age of the two pa-tient groups did not differ markedly.

Heat applied locally over the fentanyl patch[3]or a rise in body temperature[20]increases plasma fentanyl concentrations.In our patients,no differences were found in skin temperature between the normal weight and cachectic patients.No differences between the two patient groups in local blood?ow,either,were observed. In patients with profuse sweating,absorption of transdermal fenta-nyl may be impaired because patches tend to loosen from the damp skin and because droplets of moisture under the patch may impair drug absorption[20].In the present study,however, skin dampness was moderate and similar in the two patient groups and only one patient dropped out of the study because of loosening of the patch from the skin.

A close correlation between transdermal fentanyl delivery rate and plasma fentanyl concentrations has been shown both in stud-ies on acute postoperative pain[22]and chronic cancer pain [11,23].In a small study[25],the mean transdermal fentanyl bio-availability was92%,whereas in a group of29cancer patients [23]the mean bioavailability was73%with fentanyl doses from 25to200l g/h but91–97%at higher delivery rates.In our study, the cachectic patients had larger opioid doses at inclusion than the normal weight patients,probably indicating a later stage of the cancer disease and more severe pain,but possibly also indi-cating poor bioavailability of fentanyl in the patients already on transdermal fentanyl at baseline.There seems to be no concentra-tion-effect relationship for fentanyl or other strong opioids [10,15];lack of correlation between plasma fentanyl concentra-tion and analgesia is evident in the present study and that of Solassol et al.[23],where transdermal fentanyl administration re-sulted in a wide range of individual plasma fentanyl concentra-tions but provided adequate analgesia.The plasma opioid concentration is an unreliable re?ector of opioid analgesia since the opioid analgesic effect is also in?uenced by factors such as the intensity of pain,opioid tolerance and the concentration of the opioid in the central nervous system after crossing the blood–brain barrier.

Our study was small and open,limiting the generalizability of the results.We used the BMI as a single criterion for cachexia, but since cachexia is de?ned as a state of depletion,more strict inclusion criteria should probably include measurement of the pa-tient’s fat-free mass,serum albumin and C-reactive protein[17]. The effect of serum albumin levels on plasma fentanyl concentra-tions needs to be studied further.Furthermore,since some patients had been using transdermal fentanyl for pain control prior to the study whereas other patients were fentanyl na?ve,few conclusions can be made regarding the time to maximum plasma fentanyl concentrations.

The clinical implication of our study is that transdermal fenta-nyl is not the opioid of choice for cachectic cancer patients with pain.Poor transdermal absorption of fentanyl in these patients may result in inadequate analgesia despite an apparently large dose of opioid.Further research is needed to study the factors that lead to impaired skin permeability and poor fentanyl absorption in patients with cancer cachexia.The pharmacokinetics of other transdermal drugs,e.g.buprenorphine,should also be studied in cachectic patients.5.Conclusions

Absorption of transdermal fentanyl is impaired in cachectic pa-tients compared with that of normal weight patients with cancer-related pain.

Con?icts of interest

The authors have no con?icts of interest.

Acknowledgements

This study received?nancial support from the Finnish Cancer Foundation(grants to T.H.and to E.K.)and from the Helsinki Uni-versity Central Hospital Research Funds(T102010066).We thank Matti Kataja,Doctor of Science(Technology),for assistance in the statistical analysis of the data.

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一叶秋碱对芬太尼镇痛效应的影响及其机制

一叶秋碱对芬太尼镇痛效应的影响及其机制（作者:___________单位: ___________邮编: ___________）作者：王来，付海啸，刘欢欢，倪玮玮，郭济东，武静茹【摘要】目的研究芬太尼的镇痛作用与GABAA受体的关系，探讨芬太尼镇痛作用的可能机制。方法昆明种小鼠（雌性36只）按完全随机设计分成4组（n=9）：生理盐水组、一叶秋碱组（10 mg/kg）、芬太尼组（0.3 mg/kg）、一叶秋碱（10 mg/kg）+芬太尼（0.3 mg/kg）组。用热板法测定各组小鼠用药前后的痛阈。结果一叶秋碱提高芬太尼的痛阈（P＜0.05）。结论芬太尼的镇痛作用与GABAA受体部分相关。【关键词】芬太尼；一叶秋碱；镇痛；热板法芬太尼为阿片类镇痛药，其镇痛效力约为吗啡的100～180倍、哌替啶的550～1000倍［1］，并具有毒性低、对循环影响轻、时效短（15～30 min）、术后自主呼吸恢复快等优点。近年来，随着术后镇

痛技术的广泛普及，为取得良好的围术期镇痛和镇静效应，术前应用地西泮等苯二氮艹卓类药物作为镇静药物，以芬太尼等阿片类药物进行术后镇痛的患者越来越多。然而，临床研究发现，以苯二氮艹卓类药物为麻醉前用药的患者，术后镇痛所需要的吗啡剂量增加，提示苯二氮艹卓类药物可能拮抗吗啡的镇痛效应，并对此联合用药的方法提出质疑［2-3］。后经王斌等［4］进一步研究证实地西泮可拮抗芬太尼的镇痛效应，并提出其机制可能与其激动苯二氮艹卓受体后增强γ- 氨基丁酸（GABA）的作用有关。研究表明GABAA受体与阿片类μ受体分布具有相关性［5］。以上两者均提示芬太尼的镇痛效应可能与GABAA受体有关［2-5］。鉴于目前国内对芬太尼激动阿片受体的机制研究较多，而其镇痛作用与GABAA受体是否相关，笔者尚未见这方面的报道。本实验拟观察芬太尼的镇痛作用与GABAA 受体的关系，探讨芬太尼镇痛作用的非阿片受体机制。 1 材料和方法 1.1 实验动物清洁级昆明种雌性小鼠36只，体重18～25 g，由徐州医学院实验动物中心提供。 1.2 药品和仪器枸橼酸芬太尼（江苏恒瑞医药有限公司生产），一叶秋碱（江苏宜兴前进制药厂生产），分别用生理盐水稀释成所需浓度。HH-42型快速恒温显水箱（购自上海禾丰制药有限公司，批号000202）。 1.3 动物分组及处理将36只小鼠按完全随机设计分成4组（n=9）：生理盐水组（A组）、一叶秋碱（10 mg/kg）组(B组)、芬太尼（0.3

芬太尼透皮贴剂剂量的调整与换算

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剂量调整。剂量增加的幅度通常为每小时25ug，但同时应考虑附加

的疼痛治疗及患者的状态。当剂量大于每小时75ug时，可以使用1片以上本品贴剂。患者可能定时需要短效镇痛药，以缓解突发性疼痛。在本品剂量超过每小时300ug时，一些患者可能需要额外的或改变阿片类药物的用法。 3、终止治疗：除去本品贴剂后，应逐渐开始其他阿片类药物的替代疗法，并从低剂量开始缓慢加量。这是因为除去本品贴剂后，血中芬太尼浓度逐渐降低。血中芬太尼浓度下降50%，大约需要17小时甚至更长，故应逐渐停药。表1 镇痛作用等效转换参考 *依据一项将上述药物的肌内注射剂量与吗啡相比确定相对强度的单次剂量研究。口服推荐剂量来自

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舒芬因此也减少了蓄积的危险性。7倍，半衰期与芬太尼相比下降了太尼对呼吸抑制的时间短于镇痛时间，复苏时间也短于芬太尼。，是6min瑞芬太尼：是纯μ型阿片受体激动剂，清除半衰期仅恢复迅速，具有起效快，强效的阿片类镇痛药，作用时间短，超短时，无蓄积作用，麻醉深度易于控制等优点，适用于持续静脉输注。较之芬太尼和舒芬太尼，瑞芬太尼在无痛人流，无痛胃、肠镜等短小手术瑞芬太尼的镇痛作用及其副作领域中的应用已显示出明显的优越性。分钟(1 用呈剂量依赖性。盐酸瑞芬太尼剂量高达30μg/kg静脉注射内注射完毕)不会引起血浆组胺浓度的升高。瑞芬太尼对呼吸也有抑制作用，其程度亦与等效剂量的芬太尼相似，但持续时间较短，停药后恢复更快，停止输注后3-5min恢复自主呼吸。也可引起肌僵硬，但发生率较低。芬太尼注射液（国家基药）、舒芬太尼（农保目录）、瑞芬太尼（目录外）都可用于复合全身麻醉、神经安定镇痛麻醉、心血管“快通道”麻醉、门诊/日间手术麻醉（内窥镜检查、非住院手术麻醉）、术后镇痛等。舒芬太尼由于其心血管作用更为稳定，尤其适合心血管麻醉。瑞芬太尼药物消除不受肝肾功能的影响，肝肾功能不全者可选用瑞芬太尼。瑞芬太尼虽然安全系数较芬太尼和舒芬太尼高、剂量易控制，但三者作用机理相同，药效相似，是可以替代使用的。另外，芬太尼的常规用量为3-5支，合计金额为14.18-23.64元；舒芬太尼元；瑞芬太尼的常规用量为100.35支，合计金额为2的常规用量为 1-2支，合计金额为101.2-202.4元，由此可见三者中芬太尼的性价

芬太尼透皮贴剂剂量的调整与换算

创作编号： GB8878185555334563BT9125XW 创作者：凤呜大王* 芬太尼透皮贴剂剂量的调整与换算芬太尼透皮贴剂适用于中度到重度慢性疼痛以及那些只能依靠阿片类镇痛药治疗的难以消除的疼痛。本品的剂量应根据患者的个体情况而决定，并应在给药后定期进行剂量评估。本品应贴于躯干或上臂未受刺激及未受辐射的平整皮肤表面（最好选择无毛发部位）。本品开封后立即使用，使用时用手掌用力按压30秒钟，以确保贴剂与皮肤完全接触。本品可以持续贴用72小时，在更换贴剂时，应更换粘贴部位。剂量调整与换算： 1、初始计量应根据使用短效阿片药物剂量转换决定。未使用过阿片类药物的患者应以芬太尼透皮贴剂的最低剂量25ug为起始剂量，并根据疼痛缓解程度进行计量调整，调整幅度为每小时25ug，以达到最低的适合剂量。使用过阿片类药物的患者，应按下述方法将口服或肠外给药转换本品：（1）计算前24小时镇痛药用量。（2）应用表1将上述用量转换为等效的口服吗啡剂量。表1中所有肌内注射和口服剂量相当于肌内注射吗啡

10mg的等效镇痛剂量。（3）表2列出了根据24小时口服吗啡的剂量范围推算出的本品剂量。（4）如有需要，可进行调整，调整幅度为每小时25ug。 2、剂量的调整及维持：每72小时应更换一次本品贴剂。应根据个体情况调整剂量，直到达到满意的镇痛效果。如果首次用药镇痛效果不满意，可根据疼痛强度在3日后增加剂量。其后每3日进行一次剂量调整。剂量增加的幅度通常为每小时25ug，但同时应考虑附加的疼痛治疗及患者的状态。当剂量大于每小时75ug时，可以使用1片以上本品贴剂。患者可能定时需要短效镇痛药，以缓解突发性疼痛。在本品剂量超过每小时300ug时，一些患者可能需要额外的或改变阿片类药物的用法。 3、终止治疗：除去本品贴剂后，应逐渐开始其他阿片类药物的替代疗法，并从低剂量开始缓慢加量。这是因为除去本品贴剂后，血中芬太尼浓度逐渐降低。血中芬太尼浓度下降50%，大约需要17小时甚至更长，故应逐渐停药。表1 镇痛作用等效转换参考

芬太尼止痛贴

一、关于芬太尼止痛贴片（一）为长方形透明的皮肤贴片剂型。（二）含有与吗啡类似的止痛药。（三）经皮肤吸收以达止痛效果的止痛药品。（四）剂型：25ug/hr(为红字小片)及50ug/hr(为绿字大片)，如上图。二、使用对象（一）经医师评估需长期使用吗啡类止痛剂，来缓和癌症患者长期慢性、中度到重度的疼痛。（二）肠胃道阻塞不适合口服剂型的病患。三、保存方法（一）置放于室温下，不可存放于冰箱或接近热源，如阳光直接照射或电器附近皆应避免。（二）避免放在儿童或动物可取得的位置，以免误食。（三）未使用前不可事先拆开外包装，以避免成份挥发，导致药效减弱。（四）不可将整张贴片剪断，因为会使贴片内的储药囊药物流出。四、使用前注意事项（一）检查贴片有无破损，若有破损则不可使用。（二）使用部位的选择： 1.黏贴的部位应选择平坦、体毛较少之皮肤，避开皱折处，更换新贴片时，尽量选择与原部位不同之皮肤，以减少皮肤负担。 2.可选择双手上臂、前胸、后背等皮肤平坦部位，若易流汗者，建议贴于双上臂较不易脱落，有腹水之患者不建议贴于腹部。 3.避开有外伤、放射线治疗、皮肤发炎部位及淋巴水肿之皮肤。

4.不需要直接贴于疼痛部位，因贴片的止痛成份是由皮肤吸收，经血液循环达全身止痛效果。 5.若无法避免有体毛的部位，应用剪刀或电动刮胡刀去除体毛，勿使用剃刀，以避免造成皮肤完整性受损。五、使用步骤步骤1：先撕下旧片步骤2：将旧片对折放入回收袋步骤3：用清水洗净预使用的部位，待完全干燥步骤4：打开新片外包并将背胶撕下

步骤5：将新片贴上步骤6：用手掌紧按黏贴部位30秒步骤7：填写使用记录表六、使用时注意事项（一）贴片部位不可直接靠近热源，如：电毯、热水袋等。（二）洗澡时： 1.可淋浴但水温不宜太高、避免直接冲洗或搓洗贴片位置、不可浸泡热水澡，因局部加热会使药物吸收加速。 2.可于更换贴片前先洗澡，洗完后再贴上新的贴片。 3.防水措施：洗澡前可用塑料布覆盖贴片，并以透气胶带固定。

芬太尼族阿片类镇痛药的临床应用和研究

芬太尼族阿片类镇痛药的临床应用和研究安徽医科大学第一附属医院麻醉科（ 230022）张健方能新目前临床应用的芬太尼族阿片类镇痛药主要有芬太尼、阿芬太尼、苏芬太尼和瑞芬太尼等。结合本院开展的临床应用和研究工作，谈谈对此类药物的一些新认识。一芬太尼（ Fentanil ）芬太尼属人工合成的阿片受体激动剂，对U、K、6受体具有高度选择性作用。芬太尼在上世纪 60 年代合成、 70年代临床应用、 80 年代在心血管手术麻醉中应用，取代了吗啡多年来在心血管麻醉中的主导地位。 80 年代中期椎管内应用芬太尼又成为一种时尚。到目前为止，芬太尼仍然作为全身麻醉主要的阿片类镇痛药在广泛使用。 1芬太尼的药理作用特点 1）强效镇痛作用：镇痛效价强，等效价的剂量是吗啡的1 /100, 哌替啶的 1/1000；镇痛作用起效较快，静脉给芬太尼后 2 分钟起效、维持20-30 分钟。 2）对循环功能影响轻微：芬太尼镇痛剂量2-10 g/kg、麻醉剂量30-100卩g/kg很少引起低血压等血流动力学改变；由于无组胺释放，很少引起心律与心肌力的变化。 3）呼吸抑制作用明显：对呼吸驱动力、时间、呼吸肌活动均有抑制作用。主要表现为呼吸频率减慢、呼吸抑制时间长于镇痛时间。反复大量应用芬太尼可出现延迟性呼吸抑制和苏醒延迟，这主要是芬太尼的药代动力学特点所决定的。当血浆芬太尼浓度下降时，蓄积在肌肉、脂肪等组织中的芬

太尼在体内出现第二次分布高峰之故。 2卩g/kg芬太尼和0.05mg/kg咪唑安定伍用，可出现明显的呼吸抑制。 2芬太尼在临床麻醉中的应用 1）神经安定镇痛 /麻醉：眼科手术、脑立体定向手术、神经阻滞、椎管内麻醉等，在完善的局部麻醉下静脉给予 1/2 单位的氟芬合剂（Innovor ），可达到充分的神经安定镇静作用。由于氟哌利多的心脏传导阻滞、Q-T间期延长等严重的不良作用，现多以 0.04mg/kg咪唑安定取代氟哌利多，但仍应注意呼吸抑制、保证有效供氧和呼吸监测。 2）静脉复合 /静吸复合麻醉：在与镇静药、肌松药联合应用的全凭静脉麻醉或与镇静药、肌松药和吸入麻醉药联合应用的静吸复合麻醉中，芬太尼仍具有一定的应用价值和广泛的应用前景。与中时效的镇静药咪唑安定、肌松药维库溴胺等配合使用较为合理。 3）心血管麻醉：1977年Stanly应用大剂量芬太尼（＞ 50卩g/kg ）取代吗啡成功用于心脏麻醉，标志着心脏麻醉进入芬太尼时代。到了 90 年代和本世纪初，对心功能良好、手术方式较简单的心血管手术，为了缩短术后保留气管导管时间，芬太尼的应用剂量又回到了中、小剂量（＜50卩 g/kg ）实现“快通道”心血管麻醉。 4）门诊/日间手术麻醉：1-2 g/kg芬太尼、1-2mg/kg异丙酚联合应用，用于内窥镜（腹腔镜、膀胱镜、胃肠镜）检查等各种诊断及治疗的非住院手术麻醉，已经为广大患者和医生所需求。 5）其他非侵入性麻醉 / 镇痛方法：超声雾化吸入、经鼻腔喷雾、皮肤贴剂－多瑞吉，均能够达到良好的镇痛作用。

从芬太尼看镇痛药的危害

龙源期刊网 https://www.wendangku.net/doc/c86680000.html, 从芬太尼看镇痛药的危害作者：张田勘来源：《百姓生活》2019年第04期在2018年的中美貿易谈判中，我国同意将芬太尼指定为一种受控物质。放在了首要位置，这意味着向美国出售芬太尼的人，将受到中国法律规定的最高刑罚。芬太尼到底是个什么药？芬太尼是一种强效中枢性镇痛药，其作用机制类似吗啡，都是阿片受体制动剂，它的镇痛作用强度是吗啡的50?100倍。该药对人体循环系统影响比较小，已基本替代吗啡，成为目前手术麻醉最主要的镇痛剂，也在癌症病人中使用广泛。芬太尼可以激活人体内的阿片受体，因而具有欣快和舒适刺激作用。但是，当外源性的阿片物质如芬太尼进入人体时，就会让内源性快乐物质失去竞争力，导致人们大量地依赖外源性快乐物质，并且因依赖而成瘾。这其实就是物质反过来征服和控制人类的一种表现。当芬太尼过量时，首先会让人嗜睡、困惑和恶心，此后是上瘾、低血压，最后是因为快乐得难以呼吸（呼吸抑制）而死亡。芬太尼在中国的使用情况得到严格的监管，而在美国，对芬太尼等麻醉药的使用，医生能比较轻松地开出处方。目前有一款叫作泰勒宁的复方镇痛药，倒是存在滥用的趋势，该药不需要处方即可购买，长期服用有成瘾的可能性。泰勒宁的通用名为氨酚羟考酮，包含常用的退热成分对乙酰氨基酚和镇痛成分羟考酮两种成分。其中的羟考酮和芬太尼一样，同属于可能成瘾的阿片类药物。泰勒宁目前为普通处方药，其说明书上注明用于重度疼痛如肿瘤患者的癌性疼痛、其他止痛药难以控制的疼痛。有些人长期服用，既对肝肾胃肠道等有潜在的损伤风险，同时也存在潜在的成瘾风险。对非肿瘤患者的慢性疼痛，不主张长期使用泰勒宁。目前对于镇痛药，普通大众存在诸多误区。有些人认为镇痛药治标不治本，其实不然，比如非甾体类镇痛消炎药，通过消除无菌性炎症来达到镇痛目的，有治标治本的作用。另一类治疗神经病理性疼痛的抗癫痫类镇痛药，其原理是抑制神经的异常放电来治疗疼痛，也有治标治本的作用。因此，选对镇痛药很重要，必须在专业医生的指导下选用，不同的疼痛，吃不同的镇痛药。

芬太尼

分类名称一级分类：神经系统药物二级分类：镇痛药物三级分类：强镇痛药药品英文名 Fentanyl 药品别名多瑞吉、枸橼酸芬太尼、Durogesic、FentanylCitrate、Sublimaze 药物剂型 1.贴剂：25μg，50μg，75μg，100μg； 2.注射剂：0.05mg(1ml)，0.1mg(2ml)。药理作用芬太尼为阿片受体激动剂，属强效的麻醉性镇痛药。其作用机制至今尚未充分了解。可能是通过作用于中枢神经系统内的阿片受体而起效。并已观察到阿片类药可选择性地抑制某些兴奋性神经的冲动传递，发挥竞争性抑制作用，从而解除对疼痛的感受和伴随的心理行为反应。本药的作用机制与吗啡相似，但作用强度为吗啡的60～80倍。与吗啡和哌替啶相比，其作用迅速，维持时间短，不释放组胺，对心血管功能影响小，能抑制气管插管时的应激反应。芬太尼对呼吸的抑制作用弱于吗啡，但静脉注射过快也易抑制呼吸。有成瘾性。其呼吸抑制和镇痛作用可被纳洛酮拮抗。药动学口服可经胃肠吸收，但临床一般采用注射给药。静脉注射1min即起效，4min达高峰，作用持续30～60min。肌内注射约7～8min起产，可维持1～2h。肌内注射生物利用度67%，蛋白结合率80%。可透过胎盘屏障。分布容积为3.5～5.9L/kg，清除率为每分钟11～21ml/kg。主要在肝脏代谢，约10%的原形药与代谢产物由肾脏排出。半衰期约3.7h。本药透皮贴剂可持续72h系统地释放芬太尼，释放速率保持恒定。在开始使用透皮贴剂时，血清芬太尼的浓度逐渐增加，在12～24h内达到稳定，并在此后保持相对稳定达直至72h。芬太尼的血清浓度一般在首次使用透皮贴剂后的24～72h内达到峰值。血清浓度与透皮贴剂的大小成正比。在持续使用同样大小的72h贴剂时，血清浓度保持稳定。使用透皮贴剂时，皮肤温度升高可使血清芬太尼浓度升高，当皮肤温度升至40℃时，血清芬太尼浓度可能提高约1/3。取下透皮贴剂后血清芬太尼浓度逐渐下降，大约17(13－22)h内下降50%。与静脉注射相比，通过皮肤持续吸收芬太尼的方法，其药物浓度的降低比静脉注射法缓慢。适应证 1.适用于各种疼痛及外科、妇科等手术后及手术过程中的镇痛，也可用于防止或减轻手术后出现的谵妄。 2.还可与麻醉药合用，作为麻醉辅助用药。 3.与氟哌利多配伍制成“安定镇痛

-芬太尼类药物比较(1)

芬太尼族类镇痛药物比较芬太尼族类镇痛药能激活μ型阿片受体，作用强度大大高于吗啡。芬太尼效价为吗啡的100倍，而芬太尼与舒芬太尼、瑞芬太尼的效价比为1:12和1:1.2。芬太尼族类镇痛药镇痛作用主要是通过激活μ1型受体介导的，但同时也会激活部分μ2型受体和δ受体，后两者被认为主要涉及到对呼吸动力的抑制作用。芬太尼：为强效镇痛药，适用于麻醉前、中、后的镇静与镇痛，是目前复合全麻中常用的药物。作用强度为吗啡的60～80倍。由于芬太尼的脂溶性很强，易于透过血脑屏障而进入脑，也易从脑重新分布到体内其他组织，尤其是肌肉和脂肪组织。单次注射的作用时间短暂，与其再分布无关。如反复多次注射，则可产生蓄积作用，其作用持续时间延长。注药后20-90min血药浓度可出现第二个较低的峰值。因此芬太尼如反复注射或大剂量注射，可在用药后3-4h出现延迟性呼吸抑制，临床上极应引起警惕。舒芬太尼：镇痛比芬太尼更强，安全范围广。舒芬太尼对μ-受体的亲合力比芬太尼强7～10倍。舒芬太尼的镇痛效果比芬太尼强好几倍，而且有良好的血液动力学稳定性，可同时保证足够的心肌氧供应。静脉给药后几分钟内就能发挥最大的药效，药理学研究结果中，重要的一方面是心血管的稳定性，脑电图反应与芬太尼类同，同时不存在免疫抑制、溶血或组胺释放等不良反应。舒芬太尼对呼吸也有抑制作用，其程度与等效剂量的芬太尼相似，引起胸壁僵硬的作用也相

似，只是持续时间较芬太尼长。但是另一方面，舒芬太尼的时量相关半衰期与芬太尼相比下降了7倍，因此也减少了蓄积的危险性。舒芬太尼对呼吸抑制的时间短于镇痛时间，复苏时间也短于芬太尼。瑞芬太尼：是纯μ型阿片受体激动剂，清除半衰期仅6min，是超短时，强效的阿片类镇痛药，具有起效快，作用时间短，恢复迅速，无蓄积作用，麻醉深度易于控制等优点，适用于持续静脉输注。较之芬太尼和舒芬太尼，瑞芬太尼在无痛人流，无痛胃、肠镜等短小手术领域中的应用已显示出明显的优越性。瑞芬太尼的镇痛作用及其副作用呈剂量依赖性。盐酸瑞芬太尼剂量高达30μg/kg静脉注射(1分钟内注射完毕)不会引起血浆组胺浓度的升高。瑞芬太尼对呼吸也有抑制作用，其程度亦与等效剂量的芬太尼相似，但持续时间较短，停药后恢复更快，停止输注后3-5min恢复自主呼吸。也可引起肌僵硬，但发生率较低。芬太尼注射液（国家基药）、舒芬太尼（农保目录）、瑞芬太尼（目录外）都可用于复合全身麻醉、神经安定镇痛麻醉、心血管“快通道”麻醉、门诊/日间手术麻醉（内窥镜检查、非住院手术麻醉）、术后镇痛等。舒芬太尼由于其心血管作用更为稳定，尤其适合心血管麻醉。瑞芬太尼药物消除不受肝肾功能的影响，肝肾功能不全者可选用瑞芬太尼。瑞芬太尼虽然安全系数较芬太尼和舒芬太尼高、剂量易控制，但三者作用机理相同，药效相似，是可以替代使用的。另外，芬太尼的常规用量为3-5支，合计金额为14.18-23.64元；舒芬太尼的常规用量为2支，合计金额为100.35元；瑞芬太尼的常规用量为

芬太尼类药物比较

芬太尼说明书

【药品名称】通用名：芬太尼透皮贴剂商品名：多瑞吉英文名：FentanylTransdermalSystem 汉语拼音：FentainiToupitieji 主要成份：芬太尼化学名称：N-【1-(2-苯乙基)-4-哌啶基】-N-苯基-丙酰胺结构式：分子式：C22H28N2O 分子量：336.46 【性状】本品是一种长方形、透明的透皮贴剂。【药理毒理】芬太尼为一种阿片类止痛剂，主要与μ-阿片受体相互作用。它的主要治疗作用为止痛和镇静。对于首次使用阿片制剂的患者，芬太尼的最小止痛血清浓度范围为0.3-1.5ng/ml；在血清浓度高于2ng/ml以上时副作用的发生频率增加。最小有效浓度和产生毒性的浓度均随耐受性的提高而增加，耐受性的发展速度存在极大的个体差异。【药代动力学】多瑞吉在72小时的应用期间可持续地、系统地释放芬太尼。芬太尼的释放速率保持恒定。该速率由异分子聚合物释放膜及芬太尼透皮的速率所决定。在开始使用多瑞吉的时候，血清芬太尼的浓度逐渐增加，在12-24小时内达到稳定，并在此后保持相对稳定直至72小时。芬太尼的血清浓度一般在首次使用后的24至72小时内达到峰值。芬太尼的血清浓度与多瑞吉贴剂的大小成正比。在持续使用同样大小的72小时贴剂时，则血清浓度保持稳定。在取下多瑞吉贴剂后，血清芬太尼浓度逐渐下降，在大约17(13-22)小时内下降50%。与静脉注射相比通过皮肤持续吸收芬太尼的方法，其药物浓度的降低比静脉注射法缓慢。老年、恶液质或虚弱的患者其芬太尼的清除率可能会降低，因此在这些患者中，芬太尼的半衰期可能延长。芬太尼主要在肝脏代谢。约75%的芬太尼主要以代谢产物的形式排泄入尿，原形药物少于10%。约9%的使用量以代谢产物的形式排泄入粪便。血浆中未结合的芬太尼平均值估计为13-21%。【适应症】本品用于治疗需要应用阿片类止痛药物的重度慢性疼痛。