Expert consensus of the Chinese Association for the Study of Pain on pain treatment with the transdermal patch

Table 1 Advantages of transdermal drug delivery system administration

Advantages
Simple administration and improved patient compliance
Avoids hepatic first pass metabolism
Avoids direct interaction of drugs with food or other drugs in the gastrointestinal tract, which may affect drug absorption
Helps in controlled drug delivery and reduces frequency of dosing
Reduces dosage and side effects
Can be removed from the skin surface immediately
Has physical form, characteristics and identification marks so that it can be easily and quickly identified in an emergency (such as when the patient is unresponsive, unconscious or comatose)

Table 2 Factors influencing drug percutaneous absorption[10,12]

Influencing factor	Effect on transdermal drug absorption
Drug concentration	Generally, the amount of drug absorbed per unit area per unit time increases with the increase in TDDS drug concentration
Drug distribution coefficient	Drugs with both water-soluble and fat-soluble properties can be effectively absorbed through the skin. The water-soluble properties of drugs determine the concentration of the drug at the absorption site and the partition coefficient affects the rate of drug transport at the absorption site
Drug molecular weight	The ideal relative molecular weight for transdermal administration is 400 Da or less
Carrier factor	The main effects of carriers on percutaneous absorption include solubility of drugs in carriers and change of drug distribution coefficient by carrier
Site of application and time	The larger the application area (TDDS) and the longer the application time, the more the drugs are absorbed
Skin conditions	Hydration of skin helps increase percutaneous absorption. TDDS can form a closed water barrier with evaporating sweat to increase the hydration degree of the skin. It can be applied to the thin cuticle, with better absorption through the skin. When the skin is damaged, the drug will directly enter the subcutaneous tissue and capillaries, which may affect the properties of TDDS

TDDS: Transdermal drug delivery system.

Table 3 Development of transdermal patch[14]

Classification	Characteristic
First-generation transdermal patch	The drug should have suitable properties (highly potency, low molecular weight and lipophilic) to solve the problem of low oral bioavailability, to reduce the frequency of drug administration or to achieve stable drug administration
Second-generation transdermal patch	This generation of patch can promote and improve the percutaneous absorption of small molecule drugs by means of a chemical penetration enhancer, ion introduction or ultrasound
Third-generation transdermal patch	These patches help to promote percutaneous absorption of macromolecules, including therapeutic proteins and vaccines

Table 4 Pharmacokinetic characteristics of topical nonsteroidal anti-inflammatory drugs patches[23-29]

	Loxoprofen sodium	Ketoprofen	Diclofenac sodium	Flurbiprofen	Indometacin	Ibuprofen
Log P value	1.97	2.94	4.31	3.81	4.42	3.51
Cmax in ng/mL	61.20	891.36	0.81	43.00	27.00	556.00
Tmax in h	82.30	7.60	16.90	20.00	16.00	14.40
T1/2 in h	7.8	NA	NA	13.90	11.55	NA

Table 5 Pharmacology of fentanyl and buprenorphine transdermal patches[48-52]

	Fentanyl transdermal patch	Buprenorphine transdermal patch
Absorption	Bioavailability, 92%; Plasma protein binding, 79%-87%; Cmax, 2.6 μg/L; Effective time, 12.7-16.6 h; Peak time 38.1 h; AUC, 117 μg/L; H (0-72 h)	Bioavailability, 50%; Plasma protein binding, 96%; Cmax, 305 pg/mL; Onset time 21 h; Peak time, about 60 h; AUC, 20228 pg/mL
Metabolism	Metabolized by CYP3A4 in the liver, and the metabolites are basically inactive	Metabolized by CYP3A4 in the liver
Elimination	The half-life of the transdermal patch is about 17 h (13-22 h)	The half-life of the transdermal patch is 25.3 h
Mechanism	μ opioid receptor agonist	μ opioid receptor partial agonist, δ opioid receptor agonist, weak κ opioid receptor antagonist, ORL-1 agonist
Indication	Moderate to severe chronic pain and intractable pain treated with opioid analgesics	Chronic pain beyond the control of nonopioid analgesics
Dosage form specification	2.1-, 4.2-, 8.4- and 12.6-mg paste; Four specifications, lasting for 72 h	5-, 10- and 20-mg paste. Each paste is used for 7 d
Adverse reactions, > 10%	Nausea, headache, constipation, dry mouth, drowsiness, fuzzy consciousness, powerlessness, sweating	Erythema, pruritus, nausea

AUC: Area under the curve; ORL: Opioid receptor like; TDDS: Transdermal drug delivery system.

Table 6 Quality classification and definition of grade evidence

Quality level	Definition
High (a)	Very sure that the true effect value is close to the effect value estimation
Medium (b)	There is a moderate degree of confidence in the value of effect; the real effect value may be close to the estimated value, but there is still a possibility that the two are not the same
Low (c)	There is limited confidence in the effect estimates; the true effect values may not be the same as the effect estimates
Very low (d)	There is little confidence in the estimated effect; the true effect value may be quite different from the effect estimate

Table 7 Grade recommended strength classification and definition

Recommended strength	Explanation	Expression method	Expression method
Strong recommendations to support the use of an intervention	The advantages of the intervention measures outweigh the disadvantages	Recommended	1
Weak recommendations to support the use of an intervention	Interventions may have more advantages than disadvantages	Recommended use	2
Weak recommendations against the use of an intervention	Interventions may do more harm than good or the relationship between the advantages and disadvantages is not clear	Not recommended	2
Strong recommendations against the use of an intervention	The disadvantages of the intervention measures are obviously greater than the advantages	Not recommended	1

Table 8 Consensus statement of Chinese experts on pain treatment with transdermal patch

Consensus opinion	Recommended strength level of evidence
The effect of the transdermal patch in pain treatment is clear. It has the advantages of reducing adverse drug reactions and improving patient compliance	1A
NSAID transdermal patch is effective in the treatment of chronic skeletal muscle pain with few side effects, which is recommended as the first choice for the treatment of chronic musculoskeletal pain	1A
NSAIDs can be used as a combination therapy for neuropathic pain	2C
When the efficacy of transdermal NSAIDs alone is not good enough, which can be combined with analgesic drugs of another administration route, such as oral NSAIDs	2B
Opioid transdermal patch is effective in the treatment of chronic pain, but it should not be used as the initial treatment for chronic pain due to addiction and adverse reactions	1B
Opioid transdermal patch should not be used in the treatment of acute or breakthrough pain	1A
When other first-line treatment drugs are ineffective, 8% capsaicin patch can be considered for chronic pain related to peripheral neuropathic pain	1B
When other first-line treatment drugs are ineffective, 5% lidocaine patch can be considered for chronic pain related to peripheral neuropathic pain	2B

NSAID: Nonsteroidal anti-inflammatory drug.