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Valerian: An underestimated anxiolytic in the community pharmacy?
Accepted Manuscript Title: Valerian: an underestimated anxiolytic in the community pharmacy? Author: Omar Salem Gammoh Ahmed Al-Smadi Chrestian Turjman Tareq Mukattash Maher Kdour PII: DOI: Reference:
S2210-8033(16)30073-2 http://dx.doi.org/doi:10.1016/j.hermed.2016.09.001 HERMED 151
To appear in: Received date: Revised date: Accepted date:
18-3-2016 7-5-2016 7-9-2016
Please cite this article as: Gammoh, Omar Salem, Al-Smadi, Ahmed, Turjman, Chrestian, Mukattash, Tareq, Kdour, Maher, Valerian: an underestimated anxiolytic in the community pharmacy?.Journal of Herbal Medicine http://dx.doi.org/10.1016/j.hermed.2016.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Valerian: an underestimated anxiolytic in the community pharmacy?
Short title: Gammoh et al., valerian, anxiolytic
Omar Salem Gammoh1, Ahmed Al-Smadi1, Chrestian Turjman1, Tareq Mukattash2, Maher Kdour3
Principal Investigator: Omar Salem Gammoh, PhD. Assistant professor of pharmacology, department of Pharmacy, American University of Madaba, email: [email protected]. Phone: 009620790949845.
Co –author: Ahmed Al-Smadi, PhD.Assistant professor of nursing , department of sciences, American University of Madaba Co- author: Chrestian Turjman, Bsc pharmacy, American University of Madaba Co-author; Tareq Mukattash, PhD. Associate professor of clinical pharmacy and pharmacy practice. Jordan University of Science and Technology Co-author: Maher Kdour, PhD. Associate professor of clinical pharmacy. Al-Quds University.
1
Abstract: Insomnia, the inability to sleep and feel refreshed the next morning is a common problem reported as the most prevalent sleep disorder worldwide. Recently, special interest has focused on the use of herbal anxiolytics such as valerian root. In the Arab world, and particularly Jordan where it is prescribed by pharmacists, valerian root may be considered a relatively new non-prescription sleep aid. The objective of the current study was to assess pharmacists’ perception and knowledge of valerian pharmacology, explore their dispensing practice of sedatives/ hypnotics and to investigate the Jordanian customers’ behaviour and preferences towards sedative/hypnotics. Data from 568 community pharmacists surveyed in Jordan was analysed. Almost one-third of the pharmacists admitted that they were unaware of the anxiolytic mechanism of valerian and half of them described valerian as a "hypnotic" instead of an "anxiolytic". None knew that it could be hazardous to co-administer valerian with benzodiazepines. Additionally, diphenhydramine was preferred in general over valerian as a sleep aid. It was also found that pharmacists and customers thought valerian to be less effective than pharmaceutical medication in the treatment of insomnia. Our findings reflect a poor knowledge among pharmacists and the community about valerian. The authors suggest it would be beneficial to instigate measures to increase the awareness of herbal products amongst pharmacists.
Keywords: Valerian, pharmacist, insomnia
2
Introduction
Insomnia is a primary sleep disorder in which a person has difficulty falling asleep and maintaining sleep, experiences early wakening and consequently suffers impairment in the daytime for at least four weeks (Pereira et al., 2014, Unbehaun et al., 2010). Insomnia is reported to be the most prevalent sleep disorder worldwide (Attele et al., 2000, Unbehaun et al., 2010). Approximately 5% to 35% of the population in industrialised nations report sleep disturbance in their lives (Pigeon, 2010, Caldwell, 2009). Female gender, age, marital status, physical and mental illness are considered as important risk factors for insomnia (Attele et al., 2000, Pereira et al., 2014, Passarella et al., 2008). Insomniacs report impaired social, physical and cognitive functions, which affect their quality of life and could predispose sufferers to depression (Cunnington et al., 2013, Schutte-rodin et al., 2008, Pigeon, 2010). Many synthetic drugs are used to improve sleep patterns (Schutte-rodin et al., 2008). These include benzodiazepines, sedating antipsychotics, antidepressants, first generation antihistamines and melatonin receptor agonists (Schutte-rodin et al., 2008, Attele et al., 2000, Pigeon, 2010, Passarella et al., 2008, Caldwell, 2009). Benzodiazepines are the most commonly prescribed medications for short-term insomnia treatment (3-4 weeks) (Unbehaun et al., 2010, Schutte-rodin et al., 2008, 3
Attele et al., 2000, Passarella et al., 2008). Despite their clinical use as sedatives/anxiolytics, their side effects, tolerance, physical dependence and addictive potential preclude their long-term use (Unbehaun et al., 2010, Cunnington et al., 2013, Attele et al., 2000, Passarella et al., 2008). Recently, non-benzodiazepine sedative/anxiolytic therapeutic alternatives have gained attention (Caldwell, 2009). In particular, special interest is focused on the use of herbal products such as valerian root, hops, kava, chamomile, lemon balm and passionflower, which have a historical and predominant use as self-medication for treating insomnia (Unbehaun et al., 2010, Attele et al., 2000). This paper focuses on the former herbal medication, valerian root. Valeriana officinalis is a hardy perennial flowering plant (Murti et al., 2011). Although the exact chemical compounds responsible for its activities have not been fully identified, it was recently reported that valerenic acid has a role in the pharmacological action of the herb and is assumed to be GABAergic (Attele et al., 2000, Passarella et al., 2008, Murti et al., 2011, Becker et al., 2014). It is native to Europe and parts of Asia and has been cultivated in North America for commercial use to treat insomnia and anxiety as tablets or capsules (Patočka et al., 2010). Recently, valerian was introduced in Jordan as a sleep-aid product prescribed prominently by pharmacists. 4
In Jordan, the pharmacist is the primary point of contact for people who need assistance with minor health conditions that can be treated with self-care products. Pharmacists have an important role in assessing for sleep disorders such as insomnia and for providing sleep health education (Fuller et al., 2011). The lack of professional pharmaceutical supervision may expose consumers of natural products to risks; therefore, pharmacists play an important role in disseminating information about herbal products. Although valerian could be a potential anxiolytic dispensed by community pharmacists, no previously published articles have explored the basic pharmacological knowledge of community pharmacists, their beliefs, dispensing practices and customer preferences for anxiolytic/hypnotics including valerian. Therefore, the objectives of this study were to assess pharmacists’ knowledge of specific aspects of valerian pharmacology, explore their perception and dispensing practices, and also to investigate customers’ behaviour and preferences towards sedatives/hypnotics including valerian. Methods A cross-sectional survey was conducted in order to meet the study objectives.
5
Pharmacy students from the American University of Madaba approached pharmacists in four different cities: Amman, Irbid, Balqa, and Zarqa. All students were trained in a common data collection procedure and study method by one author. Sampling: Convenience pharmacies were approached in these four cities. Study objectives and methods were explained. Informed consent forms were given to potential participants. Signed consent forms were obtained from willing participants. Data was collected in October and November 2015. Ethical considerations: Ethical approval was gained from the American University of Madaba’s Ethical Review Board. Participants’ involvement in the study was voluntary, and they were told that they could withdraw from the study at any time. Study instrument: The study questionnaire included demographical details as reported in Table 1. Six questions assessed pharmacists’ knowledge about the pharmacology of Valeriana officinalis, as follows: Q1. The main indication(s) of Valeriana officinalis is/are: 0: Hypnotic, 1: Anxiolytic, 2: Antidepressant, 3: Premature ejaculation, 4: Antifatigue, 5: Enhanced memory and 6: Antioxidant. Q2. The main receptor(s)
6
responsible for Valeriana officinalis’ actions is/ are: 1: Glutamate, 2: GABA, 3: Serotonin, 4: Adrenergic, 5: Histaminic and 6: I don’t have enough information at the moment. Q3. The main proposed mechanism of action for Valeriana officinalis components is/are: 1: GABA agonist, 2: SSRI, 3: SNRI, 4: Anticholinergic, 5: Antihistaminic and 6: I don’t have enough information at the moment. Q4. Regarding its pharmacology, Valeriana officinalis can replace the following medications: 0: Benzodiazepines, 1: Antidepressants, 2: Ginseng, 3: Antiepileptic, 4: Zolpidem, 5: Antipsychotics and 6: I don’t have enough information at the moment. Q5. Valeriana officinalis should be used cautiously with: 0: Benzodiazepines, 1: Antidepressants, 3: Antiepileptic and 4: Antipsychotics. Q6. Write down available brands containingVvaleriana officinalis. Five multiple-choice questions assessed pharmacists’ beliefs and dispensing practices of Valeriana officinalis and other sedative/hypnotics. The questions were: Q1. When dispensing a medication for insomnia, the probability that you would choose a herbal product is: 0: Never, 1: Rare, 2: Sometimes, 3: Often, 4: Very often and 5: Always. Q2. If a patient with insomnia asks for a medicine, what would be your first choice: 0: Paracetamol/Diphenedramine, 1: Chlorpheniramine, 2: Valeriana officinalis, 3: Benzodiazepines, 4: Zolpidem and 5: others. Q3. In general, the main reason for dispensing a drug for insomnia is: 0: Safety, 1: Efficacy, 2: Bonus, 3: Stock liquidation, 4: Price or 5: Patient’s preference). Q4. What do you 7
think about the efficacy of Valeriana officinalis? 0: I don’t have enough information, 1: I think it’s not effective, 2: I think it’s less effective than traditional therapies, 3: I think it’s as effective as traditional therapies, 4: I think it’s more effective than traditional therapies. Q5. What do you think about the safety of Valeriana officinalis for short-term use? 0: I don’t have enough information, 1: I think it is unsafe, 2: I think it is safe to a certain extent, 3: I think it is safe and can be dispensed without prescription. Finally, six questions probed customers’ attitudes and behaviour towards Valeriana officinalis and other sedatives/hypnotics based on the pharmacist’s opinion. The questions were: Q1. How often does a patient come into your pharmacy asking for insomnia medications? 0: rare 1: < 1 per month, 2: > 1 per month, 3: > 1 per week, 4: 1 per day 5: > 1 daily. Q2. How often does a patient come into your pharmacy asking for herbal insomnia medications? 0: Never, 1: Rare, 2: Sometimes, 3: Often, 4: Very often, 5: Always. Q3. How often do patients accept taking Valeriana officinalis based on your recommendation? 0: Never, 1: Rarely, 2: Sometimes, 3: Often, 4: Always. Q4. What feedback do you receive from customers who used Valeriana officinalis? 0: No feedback, 1: Not effective, 2: Slightly effective, 3: Moderately effective, 4: Very effective. Q5. If customers refuse to take Valeriana officinalis, what options do they prefer? 0: Paracetamol/Diphenedramine, 1: Chlorpheniramine, 2: Opioids, 3: Benzodiazepines, 4: Zolpidem, 5: Others. Q6. In 8
regard to the previous questions, why do certain customers refuse to use Valeriana officinalis? 0: No specific reason, 1: They don’t like to change, 2: They think it’s not effective, 3: Other options are more economical, 4: Afraid of addiction potential. The study questions were developed by this study’s authors for the purpose of attaining the required information. The process of developing the questionnaire involved enlisting the help of five different students studying for PhDs in applied pharmacology. Meetings were conducted to reach consensus about the appropriateness of the questions. Modifications were made for some of the questions, other questions were added, and others were removed. As a result all questionnaire items were validated and had consensus for the appropriateness of each item in the questionnaire.
Sample size: This was calculated based on the total number of 2,800 community pharmacists in Jordan, 95% confidence level, and 5% confidence interval. The sample size calculation revealed the need for at least 338 pharmacists. However, for the purpose of enhancing the generalisability of the results, the authors decided to engage a number of pharmacists greater than 338.
9
Data analysis: Data was analysed using SPSS software (Version 21). Descriptive statistics were utilised in order to analyse participants’ demographical details. Chi-square test was utilised to assess differences in each of the study questions and the participants’ demographics. Results and Discussion: The present study sought community pharmacists’ knowledge regarding Valeriana officinalis, the products that contain this herb and whether they are available in the pharmacy. A sample of 568 pharmacists completed the study survey. Of those, 300 (52.8%) were female and the majority lived in Amman, the capital of Jordan. Further demographic details are presented in Table 1.
When asked about their knowledge of Valeriana officinalis and its source, the majority of respondents (n=262, 46.1%) claimed that their source of knowledge was derived from anecdotal information. Other respondents reported that they got their knowledge from the internet (n=179, 31.5%), text books (n=120, 21.1%) and journals (n=7, 1.2%). In an attempt to further assess respondents’ knowledge, more in-depth questions were asked, which are reported in Table 2.
10
We asked the participants about their beliefs and own dispensing practices regarding the products that contain Valeriana officinalis. The pharmacists were first asked about how often a patient comes into their pharmacy asking for insomnia medications. Surprisingly, 60% (N=344) reported once a week or more. Detailed results are presented in Figure 1. However, only 9% of respondents reported that patients come into their pharmacy asking for herbal insomnia medications while 4.6% reported that they are always likely to dispense a herbal medicine to treat insomnia in patients.
The
majority
of
respondents
(n=348,
61.8%)
reported
that
Paracetamol/Diphenydramine would be their first recommendation when a patients asks for their advice regarding an OTC product for insomnia. Other recommendations were as follows: Chlorpheniramine (n=83, 14.7%), Valeriana officinalis (n=102, 18.1%), Benzodiazepines (n=11, 2%) Zolpidem (n=4, 0.7%) and others (n=15, 2.7%). When we asked about the reason for choosing a medication for insomnia the majority of respondents (n=336, 60.4%) reported that safety was the main reason that made them dispense the product they chose. Other reasons were as following: efficacy (n=111, 20%), bonus (n=21, 3.8%), stock liquidation (n=14, 2.5%), price (n=14, 2.5%), and patient preference (n=60, 10.8%).
11
When we asked the participants about their own views regarding the efficacy of Valeriana officinalis in the treatment of insomnia the majority (n=212, 37.7%) thought it was less effective than the traditional therapies used to treat insomnia. Other opinions regarding the efficacy of Valeriana officinalis are presented in Figure 2. The findings of the current study revealed a poor knowledge of valerian pharmacology, together with occasional dispensing and a lesser popularity of the herb among Jordanian pharmacists and potential customers from the pharmacists’ perspectives.
More than half of the surveyed pharmacists described valerian as “hypnotic”. Our findings revealed a deep ambiguity existing within community pharmacists in Jordan between the terms “anxiolytic” and “hypnotic” as the therapeutic indication of valerian. Indeed, as an anxiolytic, valerian produces a calming effect without inducing hypnosis or reducing sleep latency (Diaper et al., 2004). According to the European Medicines Agency and the official European Community Herbal Monograph, valerian’s permitted therapeutic indication is: an "Herbal medicinal product for the relief of mild nervous tension and sleep disorders". According to the literature, valerian’s anxiolytic action leads to sedation and therefore sleep promotion. Indeed, there is no evidence depicting a direct hypnotic 12
effect of valerian as may be found with conventional hypnotics such as zolpidem (Meolie et al., 2005, Diaper et al., 2004). Although the highest percentage of surveyed pharmacists answered correctly about the valerian receptor and its proposed mechanism of action, more than one-third admitted that they “did not know”. Also, none of the surveyed pharmacists cautioned the avoidance of co-administrating valerian with other sedatives/anxiolytics such as benzodiazepines or barbiturates in order to preclude any additive GABA stimulation (Murti et al., 2011, Becker et al., 2014). This inadequate knowledge may be explained by several factors, including the lack of phytotherapy courses in pharmacy schools and poor availability of continuous pharmaceutical education after graduation, especially on newly registered pharmaceutical products. In regard to dispensing practices, a Paracetamol/Diphenhydramine combination was preferred over valerian. This was also reflected in customers’ preferences. According to the literature, antihistamines and valerian demonstrate a similar efficacy in improving sleep measures (Morin et al., 2005). Although first generation antihistamines exert a strong sedating action, they may interfere with sleep quality, lead to residual sedation, dizziness, cognitive dysfunction and anticholinergic side effects (Kamel & Gammack 2006). Valerian, on the other hand, due to its anxiolytic 13
effect, could improve subjective and objective sleep measures without residual morning sedation. This is based on the short half-life of valerenic acid (Anderson et al., 2005). The possible explanation of the pharmacists’ preferences is their previous experience and the safety associated with sedating antihistamines. The current study revealed valerian’s relatively poor popularity among Jordanians. This may be attributed to the lack of recommendations by pharmacists and other health care providers. Another possible explanation is that customers were not willing to change a “tested” drug for a new herbal therapy. Moreover, it could be that valerian did not show sufficient efficacy for insomniacs, especially ones already tolerant to benzodiazepines. Pharmacists have a leading role in the health care system based on their accessibility to patients and ability to detect and correct medication errors (Alsulami et al., 2013) Therefore, conducting a continuing education program for pharmacists in order to enhance their ability to perform pharmaceutical care and meet therapeutic objectives for their patients is essential (Shrestha et al., 2015)
14
Acknowledgments: The corresponding author would like to thank the senior pharmacy students at the American University of Madaba represented by Roya Sharaf and Su’ad Almasri. Also special thanks must go to the community pharmacists in Jordan. Finally, many thanks to Rofael for his valuable support. This work was funded by the American University of Madaba. The authors declare no conflict of interest.
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References Alsulami Z, Conroy S, Choonara I., 2013. Medication errors in the Middle East countries: a systematic review of the literature. Eur J Clin Pharmacol.69 :995-1008. Anderson GD, Elmer GW, Kantor ED, Templeton IE, Vitiello MV., 2005.Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects. Phytother Res.19801-3. Attele AS, Xie JT, Yuan CS., 2000. Treatment of insomnia: an alternative approach. Altern Med Rev.5:249-59. Becker A, Felgentreff F, Schröder H, Meier B, Brattström A.,2014. The anxiolytic effects of a Valerian extract is based on valerenic acid. BMC Complement Altern Med. 14:267. Caldwell J.,2015. Non-traditional Methods for the Treatment of Insomnia: A Mini Review. Austin J Sleep Disorder. 2 : 1007 Cunnington D, Junge MF, Fernando AT.,2013. Insomnia: prevalence, consequences and effective treatment. Med J Aust.199:S36-40. Diaper A, Hindmarch I.,2004. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res. 18:831-6. Fuller JM, Wong KK, Krass I, Grunstein R, Saini B.,2011. Sleep disorders screening, sleep health awareness, and patient follow-up by community pharmacists in Australia. Patient Educ Couns. 83:325-35. Kamel, Nabil S., and Julie K. Gammack. 2006 "Insomnia in the elderly: cause, approach, and treatment." The American journal of medicine. 119 : 463-469.
Meolie AL, Rosen C, Kristo D, et al.2005. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med. 1:173-87.
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Morin CM, Koetter U, Bastien C, Ware JC, Wooten V., 2005. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep.28:1465-71. Murti K. Kaushik M. , Sangwan Y.2011, Kaushik A. Pharmacological Properties of Valeriana Officinalis A Review. Pharmacologyonline. 641646 Passarella S, Duong MT.2008. Diagnosis and treatment of insomnia. Am J Health Syst Pharm. 65:927-34. Patočka J., Jakl J.,2010. Biomedically relevant chemical constituents of valeriana officinalis. Journal of Applied biomedicine. 8 : 11–18 Pereira C, Almeida C, Veiga N, Amaral O. ,2014.Prevalence and determinants of insomnia symptoms among schoolteachers. Aten Primaria. 46 :118-22. Pigeon WR.,2010. Diagnosis, prevalence, pathways, consequences & treatment of insomnia. Indian J Med Res. 131:321-32. Schutte-rodin S, Broch L, Buysse D, Dorsey C, Sateia M.,2008. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 4:487-504. Shrestha M, Maharjan R, Prajapati A, Ghimire S, Shrestha N, Banstola A.,2015. Assessment of knowledge and practice of community pharmacy personnel on diabetes mellitus management in Kathmandu district: a cross sectional descriptive study. J Diabetes Metab Disord.14:71. Unbehaun T, Spiegelhalder K, Hirscher V, Riemann D.,2010. Management of insomnia: update and new approaches. Nat Sci Sleep. 2:127-38.
17
35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 8.80%
12.50%
18.80%
31.60%
15.50%
12.90%
0.00% Rare
Less than 1 More than 1 More than 1 1 per day More than 1 per month per month per week per day
Figure 1. How often a patient comes into your pharmacy asking for insomnia medications
18
40.00%
37.70%
35.00% 28.80%
30.00% 25.00% 20.00%
18.70%
15.00% 10.00%
7.70%
7.10%
5.00% 0.00% I don’t have I think enough I think it's less information it's I think effective notit's Ieffective think asthan effective it's more conventional as effective conventional therapies than conventional therapies therapies
Figure 2. Respondents' views regarding the efficacy of Valeriana Officinalis
19
Table 1: Demographics of the study participants Variable Gender Male Female Age (Years)
Frequency (n)
Percent (%)
268 300
47.2 52.8
<35 35-50 >50
413 129 26
72.2 22.7 4.6
383 30 124 31
67.4 5.3 21.8 5.5
167 104 164 133
29.4 18.3 28.9 23.4
40 341 152 35
7 60 26.8 6.2
493 75
86.7 13.2
Living area Amman Balqa Irbid Zarqa
Experience in years 1 2 3 4 University rating Acceptable Good Very Good Excellent Country of study Jordan Abroad
20
Table 2: Pharmacists’ knowledge regarding Valeriana officinalis ( * indicates the correct answer) The main indication (s) of Valeriana officinalis is/are Items Freq (n) Percent (%) Hypnotic n=293 51.6% Anxiolytic * n=167 29.4% Antidepressant n=49 8.6% Premature ejaculation n=8 1.4% Anti-fatigue n=22 3.9% Enhance memory n=9 1.6% Antioxidant n=8 1.4% The main receptor(s) responsible for Valeriana officinalis actions is/ are Item Freq (n) Percent (%) Glutamate n=30 5.3% GABA* n=231 40.7% Serotonin n=79 13.9% Adrenergic n=17 3% Histaminic n=29 5.1% I don’t have enough information at n=176 31% the moment The main proposed mechanism of action for Valeriana officinalis
Item GABA agonist* SSRI SNRI Anticholinergic Antihistaminic Do not know
Freq (n) Percent (%) n=277 n=58 n=18 n=22 n=29 n=209
40% 10.2% 3,2% 3.9% 5.1% 36.8%
Regarding its pharmacology, Valeriana officinalis can replace
Item Benzodiazepines* Antidepressants
Freq (n) Percent (%) n=275 48.4% n=93 16.4% 21
Ginseng Antiepileptic Zolpidem Antipsychotics Do not know
n=16 n=11 n=84 n=15 n=66
2.8% 1.9% 14.8% 2.6% 11.6%
Valeriana officinalis should be used cautiously with
Item Benzodiazepines* Antidepressants Antiepileptic Antipsychotics None of the above
Freq (n) n=0 n=391 n=26 n=67 n=78
22
Percent (%) 0% 68.8% 4.6% 11.8% 13.7%
S2210-8033(16)30073-2 http://dx.doi.org/doi:10.1016/j.hermed.2016.09.001 HERMED 151
To appear in: Received date: Revised date: Accepted date:
18-3-2016 7-5-2016 7-9-2016
Please cite this article as: Gammoh, Omar Salem, Al-Smadi, Ahmed, Turjman, Chrestian, Mukattash, Tareq, Kdour, Maher, Valerian: an underestimated anxiolytic in the community pharmacy?.Journal of Herbal Medicine http://dx.doi.org/10.1016/j.hermed.2016.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Valerian: an underestimated anxiolytic in the community pharmacy?
Short title: Gammoh et al., valerian, anxiolytic
Omar Salem Gammoh1, Ahmed Al-Smadi1, Chrestian Turjman1, Tareq Mukattash2, Maher Kdour3
Principal Investigator: Omar Salem Gammoh, PhD. Assistant professor of pharmacology, department of Pharmacy, American University of Madaba, email: [email protected]. Phone: 009620790949845.
Co –author: Ahmed Al-Smadi, PhD.Assistant professor of nursing , department of sciences, American University of Madaba Co- author: Chrestian Turjman, Bsc pharmacy, American University of Madaba Co-author; Tareq Mukattash, PhD. Associate professor of clinical pharmacy and pharmacy practice. Jordan University of Science and Technology Co-author: Maher Kdour, PhD. Associate professor of clinical pharmacy. Al-Quds University.
1
Abstract: Insomnia, the inability to sleep and feel refreshed the next morning is a common problem reported as the most prevalent sleep disorder worldwide. Recently, special interest has focused on the use of herbal anxiolytics such as valerian root. In the Arab world, and particularly Jordan where it is prescribed by pharmacists, valerian root may be considered a relatively new non-prescription sleep aid. The objective of the current study was to assess pharmacists’ perception and knowledge of valerian pharmacology, explore their dispensing practice of sedatives/ hypnotics and to investigate the Jordanian customers’ behaviour and preferences towards sedative/hypnotics. Data from 568 community pharmacists surveyed in Jordan was analysed. Almost one-third of the pharmacists admitted that they were unaware of the anxiolytic mechanism of valerian and half of them described valerian as a "hypnotic" instead of an "anxiolytic". None knew that it could be hazardous to co-administer valerian with benzodiazepines. Additionally, diphenhydramine was preferred in general over valerian as a sleep aid. It was also found that pharmacists and customers thought valerian to be less effective than pharmaceutical medication in the treatment of insomnia. Our findings reflect a poor knowledge among pharmacists and the community about valerian. The authors suggest it would be beneficial to instigate measures to increase the awareness of herbal products amongst pharmacists.
Keywords: Valerian, pharmacist, insomnia
2
Introduction
Insomnia is a primary sleep disorder in which a person has difficulty falling asleep and maintaining sleep, experiences early wakening and consequently suffers impairment in the daytime for at least four weeks (Pereira et al., 2014, Unbehaun et al., 2010). Insomnia is reported to be the most prevalent sleep disorder worldwide (Attele et al., 2000, Unbehaun et al., 2010). Approximately 5% to 35% of the population in industrialised nations report sleep disturbance in their lives (Pigeon, 2010, Caldwell, 2009). Female gender, age, marital status, physical and mental illness are considered as important risk factors for insomnia (Attele et al., 2000, Pereira et al., 2014, Passarella et al., 2008). Insomniacs report impaired social, physical and cognitive functions, which affect their quality of life and could predispose sufferers to depression (Cunnington et al., 2013, Schutte-rodin et al., 2008, Pigeon, 2010). Many synthetic drugs are used to improve sleep patterns (Schutte-rodin et al., 2008). These include benzodiazepines, sedating antipsychotics, antidepressants, first generation antihistamines and melatonin receptor agonists (Schutte-rodin et al., 2008, Attele et al., 2000, Pigeon, 2010, Passarella et al., 2008, Caldwell, 2009). Benzodiazepines are the most commonly prescribed medications for short-term insomnia treatment (3-4 weeks) (Unbehaun et al., 2010, Schutte-rodin et al., 2008, 3
Attele et al., 2000, Passarella et al., 2008). Despite their clinical use as sedatives/anxiolytics, their side effects, tolerance, physical dependence and addictive potential preclude their long-term use (Unbehaun et al., 2010, Cunnington et al., 2013, Attele et al., 2000, Passarella et al., 2008). Recently, non-benzodiazepine sedative/anxiolytic therapeutic alternatives have gained attention (Caldwell, 2009). In particular, special interest is focused on the use of herbal products such as valerian root, hops, kava, chamomile, lemon balm and passionflower, which have a historical and predominant use as self-medication for treating insomnia (Unbehaun et al., 2010, Attele et al., 2000). This paper focuses on the former herbal medication, valerian root. Valeriana officinalis is a hardy perennial flowering plant (Murti et al., 2011). Although the exact chemical compounds responsible for its activities have not been fully identified, it was recently reported that valerenic acid has a role in the pharmacological action of the herb and is assumed to be GABAergic (Attele et al., 2000, Passarella et al., 2008, Murti et al., 2011, Becker et al., 2014). It is native to Europe and parts of Asia and has been cultivated in North America for commercial use to treat insomnia and anxiety as tablets or capsules (Patočka et al., 2010). Recently, valerian was introduced in Jordan as a sleep-aid product prescribed prominently by pharmacists. 4
In Jordan, the pharmacist is the primary point of contact for people who need assistance with minor health conditions that can be treated with self-care products. Pharmacists have an important role in assessing for sleep disorders such as insomnia and for providing sleep health education (Fuller et al., 2011). The lack of professional pharmaceutical supervision may expose consumers of natural products to risks; therefore, pharmacists play an important role in disseminating information about herbal products. Although valerian could be a potential anxiolytic dispensed by community pharmacists, no previously published articles have explored the basic pharmacological knowledge of community pharmacists, their beliefs, dispensing practices and customer preferences for anxiolytic/hypnotics including valerian. Therefore, the objectives of this study were to assess pharmacists’ knowledge of specific aspects of valerian pharmacology, explore their perception and dispensing practices, and also to investigate customers’ behaviour and preferences towards sedatives/hypnotics including valerian. Methods A cross-sectional survey was conducted in order to meet the study objectives.
5
Pharmacy students from the American University of Madaba approached pharmacists in four different cities: Amman, Irbid, Balqa, and Zarqa. All students were trained in a common data collection procedure and study method by one author. Sampling: Convenience pharmacies were approached in these four cities. Study objectives and methods were explained. Informed consent forms were given to potential participants. Signed consent forms were obtained from willing participants. Data was collected in October and November 2015. Ethical considerations: Ethical approval was gained from the American University of Madaba’s Ethical Review Board. Participants’ involvement in the study was voluntary, and they were told that they could withdraw from the study at any time. Study instrument: The study questionnaire included demographical details as reported in Table 1. Six questions assessed pharmacists’ knowledge about the pharmacology of Valeriana officinalis, as follows: Q1. The main indication(s) of Valeriana officinalis is/are: 0: Hypnotic, 1: Anxiolytic, 2: Antidepressant, 3: Premature ejaculation, 4: Antifatigue, 5: Enhanced memory and 6: Antioxidant. Q2. The main receptor(s)
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responsible for Valeriana officinalis’ actions is/ are: 1: Glutamate, 2: GABA, 3: Serotonin, 4: Adrenergic, 5: Histaminic and 6: I don’t have enough information at the moment. Q3. The main proposed mechanism of action for Valeriana officinalis components is/are: 1: GABA agonist, 2: SSRI, 3: SNRI, 4: Anticholinergic, 5: Antihistaminic and 6: I don’t have enough information at the moment. Q4. Regarding its pharmacology, Valeriana officinalis can replace the following medications: 0: Benzodiazepines, 1: Antidepressants, 2: Ginseng, 3: Antiepileptic, 4: Zolpidem, 5: Antipsychotics and 6: I don’t have enough information at the moment. Q5. Valeriana officinalis should be used cautiously with: 0: Benzodiazepines, 1: Antidepressants, 3: Antiepileptic and 4: Antipsychotics. Q6. Write down available brands containingVvaleriana officinalis. Five multiple-choice questions assessed pharmacists’ beliefs and dispensing practices of Valeriana officinalis and other sedative/hypnotics. The questions were: Q1. When dispensing a medication for insomnia, the probability that you would choose a herbal product is: 0: Never, 1: Rare, 2: Sometimes, 3: Often, 4: Very often and 5: Always. Q2. If a patient with insomnia asks for a medicine, what would be your first choice: 0: Paracetamol/Diphenedramine, 1: Chlorpheniramine, 2: Valeriana officinalis, 3: Benzodiazepines, 4: Zolpidem and 5: others. Q3. In general, the main reason for dispensing a drug for insomnia is: 0: Safety, 1: Efficacy, 2: Bonus, 3: Stock liquidation, 4: Price or 5: Patient’s preference). Q4. What do you 7
think about the efficacy of Valeriana officinalis? 0: I don’t have enough information, 1: I think it’s not effective, 2: I think it’s less effective than traditional therapies, 3: I think it’s as effective as traditional therapies, 4: I think it’s more effective than traditional therapies. Q5. What do you think about the safety of Valeriana officinalis for short-term use? 0: I don’t have enough information, 1: I think it is unsafe, 2: I think it is safe to a certain extent, 3: I think it is safe and can be dispensed without prescription. Finally, six questions probed customers’ attitudes and behaviour towards Valeriana officinalis and other sedatives/hypnotics based on the pharmacist’s opinion. The questions were: Q1. How often does a patient come into your pharmacy asking for insomnia medications? 0: rare 1: < 1 per month, 2: > 1 per month, 3: > 1 per week, 4: 1 per day 5: > 1 daily. Q2. How often does a patient come into your pharmacy asking for herbal insomnia medications? 0: Never, 1: Rare, 2: Sometimes, 3: Often, 4: Very often, 5: Always. Q3. How often do patients accept taking Valeriana officinalis based on your recommendation? 0: Never, 1: Rarely, 2: Sometimes, 3: Often, 4: Always. Q4. What feedback do you receive from customers who used Valeriana officinalis? 0: No feedback, 1: Not effective, 2: Slightly effective, 3: Moderately effective, 4: Very effective. Q5. If customers refuse to take Valeriana officinalis, what options do they prefer? 0: Paracetamol/Diphenedramine, 1: Chlorpheniramine, 2: Opioids, 3: Benzodiazepines, 4: Zolpidem, 5: Others. Q6. In 8
regard to the previous questions, why do certain customers refuse to use Valeriana officinalis? 0: No specific reason, 1: They don’t like to change, 2: They think it’s not effective, 3: Other options are more economical, 4: Afraid of addiction potential. The study questions were developed by this study’s authors for the purpose of attaining the required information. The process of developing the questionnaire involved enlisting the help of five different students studying for PhDs in applied pharmacology. Meetings were conducted to reach consensus about the appropriateness of the questions. Modifications were made for some of the questions, other questions were added, and others were removed. As a result all questionnaire items were validated and had consensus for the appropriateness of each item in the questionnaire.
Sample size: This was calculated based on the total number of 2,800 community pharmacists in Jordan, 95% confidence level, and 5% confidence interval. The sample size calculation revealed the need for at least 338 pharmacists. However, for the purpose of enhancing the generalisability of the results, the authors decided to engage a number of pharmacists greater than 338.
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Data analysis: Data was analysed using SPSS software (Version 21). Descriptive statistics were utilised in order to analyse participants’ demographical details. Chi-square test was utilised to assess differences in each of the study questions and the participants’ demographics. Results and Discussion: The present study sought community pharmacists’ knowledge regarding Valeriana officinalis, the products that contain this herb and whether they are available in the pharmacy. A sample of 568 pharmacists completed the study survey. Of those, 300 (52.8%) were female and the majority lived in Amman, the capital of Jordan. Further demographic details are presented in Table 1.
When asked about their knowledge of Valeriana officinalis and its source, the majority of respondents (n=262, 46.1%) claimed that their source of knowledge was derived from anecdotal information. Other respondents reported that they got their knowledge from the internet (n=179, 31.5%), text books (n=120, 21.1%) and journals (n=7, 1.2%). In an attempt to further assess respondents’ knowledge, more in-depth questions were asked, which are reported in Table 2.
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We asked the participants about their beliefs and own dispensing practices regarding the products that contain Valeriana officinalis. The pharmacists were first asked about how often a patient comes into their pharmacy asking for insomnia medications. Surprisingly, 60% (N=344) reported once a week or more. Detailed results are presented in Figure 1. However, only 9% of respondents reported that patients come into their pharmacy asking for herbal insomnia medications while 4.6% reported that they are always likely to dispense a herbal medicine to treat insomnia in patients.
The
majority
of
respondents
(n=348,
61.8%)
reported
that
Paracetamol/Diphenydramine would be their first recommendation when a patients asks for their advice regarding an OTC product for insomnia. Other recommendations were as follows: Chlorpheniramine (n=83, 14.7%), Valeriana officinalis (n=102, 18.1%), Benzodiazepines (n=11, 2%) Zolpidem (n=4, 0.7%) and others (n=15, 2.7%). When we asked about the reason for choosing a medication for insomnia the majority of respondents (n=336, 60.4%) reported that safety was the main reason that made them dispense the product they chose. Other reasons were as following: efficacy (n=111, 20%), bonus (n=21, 3.8%), stock liquidation (n=14, 2.5%), price (n=14, 2.5%), and patient preference (n=60, 10.8%).
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When we asked the participants about their own views regarding the efficacy of Valeriana officinalis in the treatment of insomnia the majority (n=212, 37.7%) thought it was less effective than the traditional therapies used to treat insomnia. Other opinions regarding the efficacy of Valeriana officinalis are presented in Figure 2. The findings of the current study revealed a poor knowledge of valerian pharmacology, together with occasional dispensing and a lesser popularity of the herb among Jordanian pharmacists and potential customers from the pharmacists’ perspectives.
More than half of the surveyed pharmacists described valerian as “hypnotic”. Our findings revealed a deep ambiguity existing within community pharmacists in Jordan between the terms “anxiolytic” and “hypnotic” as the therapeutic indication of valerian. Indeed, as an anxiolytic, valerian produces a calming effect without inducing hypnosis or reducing sleep latency (Diaper et al., 2004). According to the European Medicines Agency and the official European Community Herbal Monograph, valerian’s permitted therapeutic indication is: an "Herbal medicinal product for the relief of mild nervous tension and sleep disorders". According to the literature, valerian’s anxiolytic action leads to sedation and therefore sleep promotion. Indeed, there is no evidence depicting a direct hypnotic 12
effect of valerian as may be found with conventional hypnotics such as zolpidem (Meolie et al., 2005, Diaper et al., 2004). Although the highest percentage of surveyed pharmacists answered correctly about the valerian receptor and its proposed mechanism of action, more than one-third admitted that they “did not know”. Also, none of the surveyed pharmacists cautioned the avoidance of co-administrating valerian with other sedatives/anxiolytics such as benzodiazepines or barbiturates in order to preclude any additive GABA stimulation (Murti et al., 2011, Becker et al., 2014). This inadequate knowledge may be explained by several factors, including the lack of phytotherapy courses in pharmacy schools and poor availability of continuous pharmaceutical education after graduation, especially on newly registered pharmaceutical products. In regard to dispensing practices, a Paracetamol/Diphenhydramine combination was preferred over valerian. This was also reflected in customers’ preferences. According to the literature, antihistamines and valerian demonstrate a similar efficacy in improving sleep measures (Morin et al., 2005). Although first generation antihistamines exert a strong sedating action, they may interfere with sleep quality, lead to residual sedation, dizziness, cognitive dysfunction and anticholinergic side effects (Kamel & Gammack 2006). Valerian, on the other hand, due to its anxiolytic 13
effect, could improve subjective and objective sleep measures without residual morning sedation. This is based on the short half-life of valerenic acid (Anderson et al., 2005). The possible explanation of the pharmacists’ preferences is their previous experience and the safety associated with sedating antihistamines. The current study revealed valerian’s relatively poor popularity among Jordanians. This may be attributed to the lack of recommendations by pharmacists and other health care providers. Another possible explanation is that customers were not willing to change a “tested” drug for a new herbal therapy. Moreover, it could be that valerian did not show sufficient efficacy for insomniacs, especially ones already tolerant to benzodiazepines. Pharmacists have a leading role in the health care system based on their accessibility to patients and ability to detect and correct medication errors (Alsulami et al., 2013) Therefore, conducting a continuing education program for pharmacists in order to enhance their ability to perform pharmaceutical care and meet therapeutic objectives for their patients is essential (Shrestha et al., 2015)
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Acknowledgments: The corresponding author would like to thank the senior pharmacy students at the American University of Madaba represented by Roya Sharaf and Su’ad Almasri. Also special thanks must go to the community pharmacists in Jordan. Finally, many thanks to Rofael for his valuable support. This work was funded by the American University of Madaba. The authors declare no conflict of interest.
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References Alsulami Z, Conroy S, Choonara I., 2013. Medication errors in the Middle East countries: a systematic review of the literature. Eur J Clin Pharmacol.69 :995-1008. Anderson GD, Elmer GW, Kantor ED, Templeton IE, Vitiello MV., 2005.Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects. Phytother Res.19801-3. Attele AS, Xie JT, Yuan CS., 2000. Treatment of insomnia: an alternative approach. Altern Med Rev.5:249-59. Becker A, Felgentreff F, Schröder H, Meier B, Brattström A.,2014. The anxiolytic effects of a Valerian extract is based on valerenic acid. BMC Complement Altern Med. 14:267. Caldwell J.,2015. Non-traditional Methods for the Treatment of Insomnia: A Mini Review. Austin J Sleep Disorder. 2 : 1007 Cunnington D, Junge MF, Fernando AT.,2013. Insomnia: prevalence, consequences and effective treatment. Med J Aust.199:S36-40. Diaper A, Hindmarch I.,2004. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res. 18:831-6. Fuller JM, Wong KK, Krass I, Grunstein R, Saini B.,2011. Sleep disorders screening, sleep health awareness, and patient follow-up by community pharmacists in Australia. Patient Educ Couns. 83:325-35. Kamel, Nabil S., and Julie K. Gammack. 2006 "Insomnia in the elderly: cause, approach, and treatment." The American journal of medicine. 119 : 463-469.
Meolie AL, Rosen C, Kristo D, et al.2005. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med. 1:173-87.
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Morin CM, Koetter U, Bastien C, Ware JC, Wooten V., 2005. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep.28:1465-71. Murti K. Kaushik M. , Sangwan Y.2011, Kaushik A. Pharmacological Properties of Valeriana Officinalis A Review. Pharmacologyonline. 641646 Passarella S, Duong MT.2008. Diagnosis and treatment of insomnia. Am J Health Syst Pharm. 65:927-34. Patočka J., Jakl J.,2010. Biomedically relevant chemical constituents of valeriana officinalis. Journal of Applied biomedicine. 8 : 11–18 Pereira C, Almeida C, Veiga N, Amaral O. ,2014.Prevalence and determinants of insomnia symptoms among schoolteachers. Aten Primaria. 46 :118-22. Pigeon WR.,2010. Diagnosis, prevalence, pathways, consequences & treatment of insomnia. Indian J Med Res. 131:321-32. Schutte-rodin S, Broch L, Buysse D, Dorsey C, Sateia M.,2008. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 4:487-504. Shrestha M, Maharjan R, Prajapati A, Ghimire S, Shrestha N, Banstola A.,2015. Assessment of knowledge and practice of community pharmacy personnel on diabetes mellitus management in Kathmandu district: a cross sectional descriptive study. J Diabetes Metab Disord.14:71. Unbehaun T, Spiegelhalder K, Hirscher V, Riemann D.,2010. Management of insomnia: update and new approaches. Nat Sci Sleep. 2:127-38.
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35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 8.80%
12.50%
18.80%
31.60%
15.50%
12.90%
0.00% Rare
Less than 1 More than 1 More than 1 1 per day More than 1 per month per month per week per day
Figure 1. How often a patient comes into your pharmacy asking for insomnia medications
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40.00%
37.70%
35.00% 28.80%
30.00% 25.00% 20.00%
18.70%
15.00% 10.00%
7.70%
7.10%
5.00% 0.00% I don’t have I think enough I think it's less information it's I think effective notit's Ieffective think asthan effective it's more conventional as effective conventional therapies than conventional therapies therapies
Figure 2. Respondents' views regarding the efficacy of Valeriana Officinalis
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Table 1: Demographics of the study participants Variable Gender Male Female Age (Years)
Frequency (n)
Percent (%)
268 300
47.2 52.8
<35 35-50 >50
413 129 26
72.2 22.7 4.6
383 30 124 31
67.4 5.3 21.8 5.5
167 104 164 133
29.4 18.3 28.9 23.4
40 341 152 35
7 60 26.8 6.2
493 75
86.7 13.2
Living area Amman Balqa Irbid Zarqa
Experience in years 1 2 3 4 University rating Acceptable Good Very Good Excellent Country of study Jordan Abroad
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Table 2: Pharmacists’ knowledge regarding Valeriana officinalis ( * indicates the correct answer) The main indication (s) of Valeriana officinalis is/are Items Freq (n) Percent (%) Hypnotic n=293 51.6% Anxiolytic * n=167 29.4% Antidepressant n=49 8.6% Premature ejaculation n=8 1.4% Anti-fatigue n=22 3.9% Enhance memory n=9 1.6% Antioxidant n=8 1.4% The main receptor(s) responsible for Valeriana officinalis actions is/ are Item Freq (n) Percent (%) Glutamate n=30 5.3% GABA* n=231 40.7% Serotonin n=79 13.9% Adrenergic n=17 3% Histaminic n=29 5.1% I don’t have enough information at n=176 31% the moment The main proposed mechanism of action for Valeriana officinalis
Item GABA agonist* SSRI SNRI Anticholinergic Antihistaminic Do not know
Freq (n) Percent (%) n=277 n=58 n=18 n=22 n=29 n=209
40% 10.2% 3,2% 3.9% 5.1% 36.8%
Regarding its pharmacology, Valeriana officinalis can replace
Item Benzodiazepines* Antidepressants
Freq (n) Percent (%) n=275 48.4% n=93 16.4% 21
Ginseng Antiepileptic Zolpidem Antipsychotics Do not know
n=16 n=11 n=84 n=15 n=66
2.8% 1.9% 14.8% 2.6% 11.6%
Valeriana officinalis should be used cautiously with
Item Benzodiazepines* Antidepressants Antiepileptic Antipsychotics None of the above
Freq (n) n=0 n=391 n=26 n=67 n=78
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Percent (%) 0% 68.8% 4.6% 11.8% 13.7%