Received: 27 September 2022 Revised: 13 December 2022 Accepted: 15 December 2022

DOI: 10.1002/bmc.5591

REVIEW

Pharmacokinetic and pharmacodynamic herb–drug

interactions of common over-the-counter pain medications

Chung-Kai Sun 1 | Tung-Hu Tsai 1,2,3

1
Institute of Traditional Medicine, College of
Medicine, National Yang Ming Chiao Tung Abstract
University, Taipei, Taiwan
Pain is one of the most common reasons for seeking medical intervention, and self-
2
Graduate Institute of Acupuncture Science,
China Medical University, Taichung, Taiwan medication with over-the-counter medications and/or traditional herbal remedies
3
School of Pharmacy, Kaohsiung Medical has become increasingly popular. In this review, original articles on understanding
University, Kaohsiung, Taiwan
possible herb–drug interactions between traditional herbs and four major pain
Correspondence medications—acetaminophen, aspirin, ibuprofen and naproxen—are compiled and
Professor Tung-Hu Tsai, Institute of
analyzed. In terms of analytical methods, high-performance liquid chromatography
Traditional Medicine, School of Medicine,
National Yang Ming Chiao Tung University, using an isocratic eluent system coupled to biological sample clean-up is the most
155, Li-Nong Street Section 2, Taipei common, while a wide variety of detectors have been observed, including a photodi-
112, Taiwan.
Email: thtsai@nycu.edu.tw ode array, variable wavelength detector, electrochemical detector and tandem mass
spectrometer. Both synergistic and anti-synergistic effects were observed for acet-
Funding information
National Science and Technology Council, aminophen and aspirin, while only synergistic effects have been found for naproxen.
Grant/Award Numbers: NSTC 111-2321-B-
Currently, no interactions have been reported for ibuprofen.
A49-007, NSTC 111-2113-M-A49-018;
College of Medicine, National Yang Ming Chiao
Tung University, Taipei, Taiwan KEYWORDS
biomedical chromatography, biomedical separation, herb–drug interactions, pharmacodynamics,
pharmacokinetics

1 | I N T RO DU CT I O N cognition, attention, functional and subjective disability, and system-

of-care issues (Gatchel et al., 2014; Loeser & Melzack, 1999). Upon
The physiological sensation of pain, one of the most common reasons the nociception of pain, emotion is the immediate reaction to
one seeks medical intervention (Loeser & Melzack, 1999; Schappert & it. Cognition can further attach meaning to this emotional experience,
Burt, 2006), has been with us throughout human history. Indeed, fossil further triggering additional emotional and behavioral reactions that
evidence suggests that Neanderthals used self-medication for amplify the experience of pain, leading to a negative loop of nocicep-
attempted treatment of dental abscesses (Weyrich et al., 2017). Pain tion, pain, distress and disability (Gatchel et al., 2014). Perhaps the
can be acute, chronic or transient (Loeser & Melzack, 1999). Acute International Association for the Study of Pain sums it up best: “Pain
pain is caused by body tissue injuries and the result of activation of is an unpleasant sensory and emotional experience associated with
the nociceptive transducer at the site of local tissue damage (Loeser & actual or potential tissue damage, or described in terms of such dam-
Melzack, 1999), generally classified as nociceptive, inflammatory and age” (Merskey, 1986).
pathological (Woolf, 2010). Chronic pain is commonly triggered by an It has been reported that roughly 20% of US population suffers
injury or disease, but can be perpetuated by other factors (Loeser & from chronic pain; this percentage correlates positively with age, with
Melzack, 1999), usually classified as nociceptive, neuropathic and those 65 years and older having an over 30% chance of experiencing
nociplastic (Cohen et al., 2021). On the other hand, transient pain is chronic pain (Zelaya et al., 2020). This same trend was also observed
defined as the activation of nociceptive transducers in the absence of in other countries (Azevedo et al., 2012). With an aging population
tissue damage (Loeser & Melzack, 1999). among the industrialized nations, chronic pain is quickly becoming a
In addition to the physiological aspect, pain is also strongly influ- major health problem. Evidently, analgesics are the most frequently
enced by psychological and socioeconomic factors such as emotion, prescribed therapeutic drugs for both physician office visits and

Biomedical Chromatography. 2023;37:e5591. wileyonlinelibrary.com/journal/bmc © 2023 John Wiley & Sons Ltd. 1 of 8
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hospital emergency department visits, according to the US National bioavailability of orally administered acetaminophen by approximately
Centre for Health Statistics (Cairns et al., 2018; Santo & 10% (Samojlik et al., 2016). Gwilt et al. found that regular consump-
Okeyode, 2018). tion of garlic can slightly increase the metabolism of acetaminophen
Aside from prescription medications, over-the-counter (OTC) or (Gwilt et al., 1994). Kaempferia parviflora, a widely used supplement/
self-medication is also a major component of pain management herbal medicine for vitalization, was found to be able to increase the
(Goetz et al., 2020). Examples of self-medication were observed from clearance and elimination rate constant, and decreases the bioavail-
our ancient relative the Neanderthal (Weyrich et al., 2017), and more ability of acetaminophen (Mekjaruskul & Sripanidkulchai, 2020).
recently acknowledged by the World Health Organization as an However, galgeuntang, a traditional herbal medicine commonly
important contribution to the health and well-being of humans (World coadministered with acetaminophen for common cold, was found to
Health, 1998). A recent cross-sectional descriptive observational be able to increase the overall concentration of acetaminophen by
study conducted in Spain showed that 78.9% of the respondents had 16.4% (Tran et al., 2020). While kava, an aqueous extract of the roots
previously taken or were currently taking OTC drugs, and the majority of Piper methysticum, has been found to potentiate acetaminophen-
of drugs consumed were analgesics at 49.1% (Sánchez-Sánchez induced hepatotoxicity at a dosage level that is otherwise harmless
et al., 2021). Similar trends were observed elsewhere in the world, in (Narayanapillai et al., 2014). In addition, Hedera helix extract is able to
both developing countries (Ayalew, 2017; Shafie et al., 2018; protect against acetaminophen-induced liver damage (Moshaie-
Tesfamariam et al., 2019) and developed countries (Alkhalidi Nezhad et al., 2019).
et al., 2021; Karlowicz-Bodalska et al., 2016; Kiza et al., 2021; Finally, a case report in 1996 described a patient with spontane-
Sarganas et al., 2015). ous bilateral subdural hematomas as a result of chronic Ginkgo biloba
With the rise of self-medication, the use of natural, supplemental ingestion combined with acetaminophen administration, possibly
and herbal remedies has become prominent, with or without OTC or owing to the combined inhibitory effect on platelet aggregation by
prescription drugs. In Taiwan, it was estimated that approximately ginkgolide B in ginkgo with acetaminophen (Rowin & Lewis, 1996). A
10% of the population regularly utilizes traditional or complementary compilation of notable herb–drug interactions of acetaminophen is
medicines (Shih et al., 2009); similar numbers were observed in China depicted in Table 1.
(14%) (Aw et al., 2019), Malaysia (21.5%) (Kaur et al., 2019), Although acetaminophen is generally a safe and effective drug
South Korea (25.4%) (Park et al., 2021) and India (13%) (Pengpid & when properly used, it nevertheless has the possibility of inducing
Peltzer, 2021); and approximately 70% of the physicians in Japan reg- liver toxicity. It is one of the most common causes of acute liver fail-
ularly prescribe Kampo drugs for their patients (Yamakawa ure in the USA (Ostapowicz et al., 2002), and was classified by the
et al., 2013). Among health conditions, pain relief has consistently FDA as the category of drugs with the greatest potential to cause
been the main reason for self-medication, using either OTC drugs drug-induced liver injury (Chen et al., 2016). In this review, two com-
(Perrot et al., 2019) or herbal remedies (Lin et al., 2015). monly used herbal medicines, galgeuntang and kava, were found to be
In light of the importance of self-medication for pain conditions, able to increase acetaminophen concentration, which could potentiate
we gathered current understanding of possible herb–drug interactions liver damage at otherwise harmless doses of the drug.
between traditional medicines and the most commonly used OTC pain In the scope of this review, the separation of acetaminophen was
medications, namely acetaminophen/paracetamol, aspirin, ibuprofen performed solely with high-performance liquid chromatography
and naproxen, compiling the analytical methods and final verdict on (HPLC). More varieties of detectors were observed for the choices
possible interactions. namely, photo diode array (PDA), variable wavelength detector
(VWD), electrochemical detector and tandem mass spectrometer
(MS/MS).
2 | INTERACTIONS OF COMMON OTC Variable wavelength and PDA detectors utilize the same basic
P A I N K I L L E R S A N D H E R B A L R E M E DI ES technology of a deuterium light source capable of producing an ultra-
violate–visible (UV–vis) spectrum. The main difference between the
2.1 | Acetaminophen VWD and PDA is that the former uses a monochromator to select for
a specific wavelength in the spectrum for selective detection, while
Acetaminophen, or paracetamol, was first introduced to the market in the latter monitors the entire UV–vis spectrum (Nikolin et al., 2004).
1955. It is an analgesic and antipyretic drug with minimal anti- Variable wavelength and PDA detectors offer easy to use, reliable
inflammatory effects. Although its exact mechanism of action is not detection methods that are nondestructive; however, they require the
fully understood, it is one of the most commonly indicated analgesic target molecule to possess chromophoric activities within the UV–vis
drugs on the World Health Organization analgesic ladder, and is safe spectrum. Furthermore, closely related compounds with similar
for short-term and long-term use
źwiak-Bebenista
(Jo & absorption profiles cannot be easily distinguished by VWD or PDA
Nowak, 2014). It has been described as one of the top OTC drugs that detectors, unlike MS/MS. A sample chromatogram using HPLC and
are co-administered with Chinese herbal products (Chen et al., 2013). PDA for the analysis of acetaminophen is depicted in Figure 1.
In terms of herb–drug interactions, Samojlik et al. found that the MS/MS uses electromagnetic forces to select for specific particles
essential oil of anise seed (Pimpinella anisum L., Apiaceae) reduces the based on its mass-to-charge ratio, and a collision chamber that
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SUN and TSAI 3 of 8

T A B L E 1 Compilation of synergistic and antagonistic herb–drug interactions between herbal products and acetaminophen, including
interacted herbs, analytical methods and a brief explanation of results

Type of Column and separation

interaction Interacting herbs Analytical methods method Result Reference
Synergistic Galgeuntang herbal HPLC–MS/MS Gemini-C18 (5 μm, Area under the Tran et al. (2020)
formula 50  4.6 mm) concentration–time curve
Isocratic 0.5% formic acid– (AUC) increased by
methanol, 20:80 (v/v) 16.4%
Anxiolytic kava (Piper Liver enzymatic N/A Potentiated Narayanapillai
methysticum) biomarker analysis acetaminophen-induced et al. (2014)
Histopathology hepatotoxicity
hematoxylin and
dosin staining
Ivy (Hedera helix) Colorimetric N/A Antioxidant and Moshaie-Nezhad
enzymatic assay hepatoprotective against et al. (2019)
kit acetaminophen-induced
Histopathology liver damage
xylene staining
Antagonistic Aniseed (Pimpinella HPLC–diode array SUPELCOSIL LC-18 column Decreased peak plasma Samojlik et al.
anisum L., Apiaceae) detection assay (5 μm, 150  2.1 mm) concentration and (2016)
Isocratic 0.1 M acetate bioavailability
(pH = 3.6)–
acetonitrile = 90:10 (v/v)
Garlic (Allium sativum) HPLC–PDA Phenomenex Slight increase in sulfate Gwilt et al.
HPLC– 300  3.9 mm with conjugation of (1994)
electrochemical 10 μm Bondclone 10 C18 acetaminophen
detection packing
Isocratic 7% methanol and
0.75% acetic acid in 0.1 M
KH2PO4
Krachaidum or Thai HPLC–variable Eclipse XDB-CN C18 Decreased AUC, maximum Mekjaruskul and
black ginger wavelength column (5 μm, concentration and half- Sripanidkulchai
(Kaempferia parviflora) detection 4.6  150 mm) life; increased clearance (2020)
Isocratic acetonitrile– and elimination rate
phosphate buffer constant
solution (pH 4.0), 5:95
(v/v)

F I G U R E 1 Samples of HPLC–PDA chromatogram of acetaminophen. (A) Blank brain dialysate; (B) blank brain dialysate spiked with 1.0 μg/ml
acetaminophen; and (C) brain dialysate sample collected at 120 min, containing 0.6 μg/ml acetaminophen. The analytical system consisted of
Shimadzu LC-20 AD automatic pump, a SIL-20 AC autosampler, a DGU-20A3 online degasser, SPD-M20A photodiode array detector and a
Purospher STAR RP-8 endcapped (4.0  250 mm, 5 μm). The mobile phase consisted of: (A) 10 mM Na2HPO4 (pH = 6.8, adjusted by H3PO4); and
(B) acetonitrile with a ratio of A:B = 30:70 in isocratic elution mode. Peak 1 depicts the signal of acetaminophen detected at a UV wavelength of
247 nm. Retention time, 5.0 min; run time, 6.1 min.

produces unique fragmentations for each molecule. It can be config- reproducible and can achieve a lower detection limit compared with
ured to detect small molecules, as well as larger molecules such as pep- VWD and PDA, at the cost of more expensive equipment and possible
tides and proteins (Zhang et al., 2016). MS/MS is highly sensitive and interference from matrix ionization effects (Pitt, 2009; Seger, 2012).
 10990801, 2023, 7, Downloaded from https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/bmc.5591 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 8 SUN and TSAI

Electrochemical detection is a specialized detection method for pharmacokinetic or pharmacodynamic interactions with aspirin when
the analysis of neurotransmitters and their metabolites, utilizing the taken together (Shaw & Tsai, 2012). A compilation of notable herb–
oxidation/reduction potentials of the particles to achieve detection drug interactions with aspirin are shown in Table 2.
(Dong, 2019; Yap et al., 2010). Aspirin poisoning, also known as salicylate poisoning, can be
caused by the acute over-ingestion of aspirin or other salicylates con-
taining products such as wintergreen oil and bismuth subsalicylate.
2.2 | Aspirin More than 21,000 cases of salicylate poisoning were reported in 2004
alone, and approximately two-thirds of the cases required hospital
Aspirin, also known as acetylsalicylic acid, can trace its roots back to treatment (Watson et al., 2005). The acute toxicity of aspirin is consid-
the use of willow bark by ancient Sumerians and Egyptians more than ered to be 150 mg/kg of body mass (Chyka et al., 2007). Identifying
3,500 years ago for pain and fever relief. It has been commercially synergistic herb–drug interactions is helpful in the prevention of acci-
available for more than 100 years and is currently used to reduce pain, dental poisoning.
fever and inflammation, as well as to long-term prevention of various Aspirin is also used as a long-term preventive treatment of cardio-
cardiovascular diseases owing to its anti-platelet efficacy vascular diseases, so its interactions with commonly used herbal prod-
(Desborough & Keeling, 2017). It is one of the most widely used medi- ucts are of great concern. Two experiments, Shaw & Tsai (2012) and
cations globally, with an estimated 40,000 tons consumed each year Yoo et al. (2018), have been conducted in relation to this, and so far
(Warner & Mitchell, 2002). With such a large rate of consumption, co- no negative effect has been observed. However, long-term use of
administration with traditional herbs is inevitable. aspirin can also lead to upper gastrointestinal toxicity (Lavie
When used together with mixture of Salvia miltiorrhiza and et al., 2017). This is an area currently lacking relevant research, as no
Carthamus tinctorius (Danhong injection), a herbal injection frequently experiment have been performed on herb–drug interactions on aspirin
prescribed with aspirin, the plasma concentration of aspirin was signif- absorption or negative gastric effects.
icantly increased by 1.37 times, and its renal excretion decreased by The analysis and separation of aspirin were primarily performed
32.5% (Li et al., 2020). Co-administration of the pair of S. miltiorrhiza through HPLC coupled with MS/MS, with one case of ultra high-
(Danshen) and Pueraria lobata (Willd.) ohwi or Pueraria thomsonii benth performance liquid chromatography (UHPLC) and gas chromatogra-
(Gegen) was found to be able to significantly increase maximum con- phy (GC) each. Typically, UHPLC utilizes a column with particle size
centrations of both aspirin and its metabolite salicylic acid, and signifi- <2 μm, while HPLC usually utilizes 3–5 μm particles in their column.
cantly decrease the concentration of thromboxane B2, as well as the The smaller particle size of UHPLC meant that the column could be
prothrombin time of aspirin (Zhang et al., 2020; Zhou et al., 2012). packed more tightly, shortening the diffusion path of analytes and the
Similarly, co-administration of Radix Pueraria Lobata (Gegen) and stationary phase, resulting in higher separation efficiency and resolu-
Radix Angelica Sinensis (Danggui) was found to be able to significantly tion (Nahar et al., 2020). Columns of UHPLC tend to be shorter, usu-
alter the pharmacokinetics of aspirin, prolonging its half-life in blood ally 50–100 mm with an internal diameter of 2.1 mm, and operate
and total bioavailability (Xiao et al., 2019). Panax notoginseng saponin- with a lower flow rate of mobile solvents at a much higher pressure
based drugs are often prescribed together with aspirin for the preven- compared with HPLC, ultimately leading to a higher throughput envi-
tion of atherosclerosis. Sun et al. found that P. notoginseng saponin- ronment. While HPLC is slower and with lower resolution, it is more
based drugs could inhibit the hydrolysis of aspirin during intestinal economical and forgiving for new users (Nahar et al., 2020; Varma
absorption, leading to an increase in its bioavailability (Sun et al., 2011).
et al., 2018,b) and the synergistic pharmacodynamic effect of the two Gas chromatography separates the analyte mainly through the
was confirmed in a blood stasis rat model (Sun et al., 2021). difference in volatilities; thus it requires the analyte be stable at high
Dai et al. found that aspirin was able to significantly alter the temperature (around 300 C). Therefore it is only suitable for the anal-
absorption, distribution and disposition of two key active compounds ysis of small molecules. Compared with liquid chromatography, GC
of the herbal formula Xuesaitong, while the herbal formula did not has the advantage of lower operational and maintenance costs
exert a significant effect on aspirin (Dai et al., 2017). (Dorman et al., 2010; Haggarty & Burgess, 2017).
Bojungikkitang, or Buzhongyiqitang, is a herbal formula frequently
prescribed for patients with ischemic stroke, and some of its herbal
components have been reported to interact with antiplatelet drugs 2.3 | Ibuprofen and naproxen
(Gao et al., 1992; Wang et al., 2003; Wu et al., 2002; Xu et al., 1999).
However, Yoo et al. found that the formula itself does not interact Ibuprofen and naproxen are two of the most commonly used nonste-
with aspirin nor salicylic acid, in terms of both pharmacokinetic param- roid anti-inflammatory drugs, working through the inhibition of cyclo-
eters and pharmacodynamics with regard to platelet aggregation and oxygenase (COX) isoenzymes, COX-1 and COX-2, producing
TxB2 concentration in healthy subjects compared with ischemic stroke analgesic, antipyretic and anti-inflammatory activities (Rao &
subjects (Yoo et al., 2018). In 2012, Shaw and Tsai found that bu- Knaus, 2008). Research on the herb–drug interaction with ibuprofen
yang-huan-wu-tang, a common herbal formula prescribed for the and naproxen is relatively sparse compared with that on acetamino-
treatment and prevention of transient ischemic stroke, had no phen and aspirin.
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SUN and TSAI 5 of 8

T A B L E 2 Compilation of synergistic and antagonistic herb–drug interaction between herbal products and aspirin, including interacted herbs,
analytical methods and brief explanation of results

Type of Analytical Column and separation

interaction Interacting herbs method method Result Reference
Synergistic Danggui (Angelica Sinensis) HPLC–MS/MS Zorbax Eclipse XDB-C18 Increased systemic exposure Xiao et al.
Enzymatic column (5 μm, of aspirin, decreased (2019)
activity 4.6  250 mm) prothrombin time
analysis Positive ion –acetonitrile–
RT-PCR 0.5% acetic acid, 80:20
Western blot (v/v)
Negative ion – acetonitrile–
0.5% acetic acid, 85: 15
(v/v)
Danhong injection (Salvia Enzymatic assay N/A Increased plasma Li et al.
miltiorrhiza and Carthamus Protein assay concentration by 1.37 (2020)
tinctorius) Hematoxylin– times, decreased renal
eosin staining excretion by 32.5%
Danshen (S. miltiorrhiza), HPLC–MS/MS Agilent Eclipse XDB-C18 Increased maximum Zhou et al.
Gegen (Pueraria lobata Prothrombin column (5 μm, concentration and AUC of (2012)
[wild.] Ohwi or Pueraria time assay 250  4.6 mm) aspirin and its metabolite
thomsonii Benth) Gradient with 0.5% acetic salicylic acid, significantly
acid in water, and 0.5% decreased prothrombin time
acetic acid in acetonitrile
HPLC–MS/MS Agilent Eclipse XDB-C18 Moderate increase in AUC of Zhang et al.
Immunosorbent column (5 μm, aspirin, reduction in (2020)
ELISA 250  4.6 mm) systemic thromboxane B2
Gradient with 0.5% acetic
acid in water, and 0.5%
acetic acid in acetonitrile
Gegen (P. lobata [wild.] Ohwi HPLC–MS/MS Zorbax Eclipse XDB-C18 Increased systemic exposure Xiao et al.
or Pueraria thomsonii Benth) Enzymatic column (5 μm, of aspirin, decreased (2019)
activity 4.6  250 mm) prothrombin time
analysis Positive ion –acetonitrile–
RT-PCR 0.5% acetic acid, 80:20
Western blot (v/v)
Negative ion – acetonitrile–
0.5% acetic acid, 85: 15
(v/v)
Sanqi (Panax notoginseng) GC–MS Rxi-5 MS capillary column Increased whole blood Sun et al.
saponins (0.25 μm, 30 m  250 μm) viscosity, platelet (2021)
Oven setting: aggregation rate, improved
80 C for 2 min increased to metabolism disorder owing
300 C at 12 C/min, held to blood stasis
for 4.5 min
Increased to 320 C at 40 C/
min, held for 1 min
Antagonistic Xuesaitong herbal formula UHPLC–MS/ Phenomenex Gemini C18, Decreased AUC of Dai et al.
MS (3 μm, 100  2.0 mm) notoginsenoside R1, (2017)
0.1% Formic acid– decreased AUC and half-life
methanol, 20:80 (v/v) of ginsenoside Rg1

Abbreviations: ELISA, Enzyme-linked immunosorbent assay; RT-PCR, Reverse transcription polymerase chain reaction.

A clinical trial involving eight male participants found that 3 weeks Unani and Ayurvedic herb commonly prescribed for its hepatopro-
of St John’s wort pretreatment had no significant effect on the phar- tective, antifertility, antimalarial and antidiabetic properties, was
macokinetics of ibuprofen (Bell et al., 2007). found to be able to decrease the peak concentration, time to peak
Ortiz et al. found that when naproxen was administered with concentration and area under the curve of naproxen when
citral, a main component of citrus fruit peel oil, the combination co-administered; on the other hand, andrographolide, one of the
produced a synergistic interaction, boosting the anti-inflammatory active constituents of A. paniculate Nees, produced a significant
effect and reducing possible gastric damage by naproxen (Ortiz synergistic anti-arthritic activity in a pharmacodynamic study (Balap
et al., 2010). Andrographis paniculata Nees (Acanthacae), a traditional et al., 2017).
 10990801, 2023, 7, Downloaded from https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/bmc.5591 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [26/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 8 SUN and TSAI

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