Chapter 37 Polypharmacy and pain management
OVERVIEW
Herbal medicines and other complementary therapies are currently experiencing a renewed interest and popularity in developed nations worldwide.1–3 This increased trend in usage suggests that adverse drug–herb interactions may be of significant public health consequence,4 and highlights the importance of sustained pharmacovigilance and evidence based appraisal with the concurrent use of herbs and drugs in a clinical setting.5
Statistics
The Adverse Drug Reactions Advisory Committee (ADRAC) of the Australian Therapeutic Goods Administration received their first report of an adverse drug reaction from a complementary medicine in 1979. Since this time, some 988 reports of suspected adverse drug reactions to herbal medicine have been collected in Australia. As of September 2008, there have been 205,787 reported adverse drug reactions to all forms of medicine.6 While reported statistics on documented herbal adverse drug reactions can be viewed as being comparatively low in contrast to orthodox medications, this may be a reflection of both the relative safety of complementary medicines and the under-reporting of potential drug–herb interactions to regulatory agencies.7,8 Complementary practitioners must remain assiduous in identifying and reporting suspected adverse drug reactions to the regulatory authorities.
Drug–herb interaction mechanisms
Given the multifarious array of substances currently used as medicines it is not surprising that this correlates with many complex factors that can modify drug responses. Current pharmacological opinion suggests that three heterogeneous interaction mechanisms exist: pharmacokinetic, pharmacodynamic and physicochemical models7,9 (see Figure 37.1).
Figure 37.1 Interaction mechanisms
Source: Adapted from Brown L, cohen M. Herbs and natural supplements. 2nd edn. Marrickville Elsevier, 2007.
‘Pharmacokinetics’ is defined as the quantitative study of the absorption, distribution, metabolism and excretion of a medicine by the body (that is, the effects the body has on the medicine).10 Pharmacokinetic interactions occur when there is a modification to any of the four aforementioned processes, resulting in a change in the concentration
of drug at target tissues or receptor sites.7 Herbal medicines have the ability to modify the pharmacokinetic profile of a drug by either increasing or reducing its availability within the body and therefore modifying biochemical and physiological responses. Representative examples of pharmacokinetic interactions include the inhibition/induction of certain isoenzymes of the hepatic cytochrome P450 system (particularly 1A2, 2D6 and 3A4), or the inhibition/induction of the drug transporter P-glycoprotein (P-gp). As interactions of this model are largely unpredictable11 they are of far greater clinical concern in patients taking pharmaceutical medicines, especially those with a narrow therapeutic index (see the box above). Other factors such as age-related changes to pharmacokinetics due to physiological deterioration, individual variability, patient constitution, reduced homeostatic mechanisms, gender, body composition, pregnancy and organ function can also affect drug response,9,12–15 and should be carefully considered in the assessment of potential drug–herb interactions.16
‘Pharmacodynamics’ is concerned with the biochemical and physiological effect the drug has upon the body and includes the relationship between drug concentration and the magnitude of drug effect. Pharmacodynamic interactions transpire when one drug alters the sensitivity or responsiveness of tissues to another drug via receptor binding affinity and intrinsic activity, resulting in additive (agonistic), synergistic or antagonistic drug effects.7 These drug effects have both positive and negative clinical repercussions, with synergistic and additive interactions frequently being used to improve patient outcomes.17 Different to pharmacokinetic interactions, pharmacodynamic interactions may theoretically predictable and can be identified by analysing the therapeutic profiles and mechanisms of action of both the drugs and the herbs used.
The physicochemical model represents the interaction of substances that have conflicting physical or chemical properties. Physicochemical interactions can have a positive or negative effect upon the absorption of one or both substances and their subsequent assimilation within the body. Examples of this type of interaction extend to herbal substances high in tannins, polyphenols, mucilages and saponins,17 and also metal ions via the process of chelation. Decreases or increases in absorption based on these substances are of particular importance when narrow therapeutic index drugs and alkaloid-based herbs or medications are being used.
Challenges
The evidence available to guide naturopaths in the decision-making process for the assessment of drug–herb interactions is multifaceted and incorporates a variety of resources including human clinical trials, in vivo studies and adverse drug reaction database entries (see Table 37.1). Clinical adverse events that have been ascribed to drug–herb interactions are further complicated by such realities as botanical substitution (i.e. either intentional or accidental) of a different plant species and contamination of the herb with pharmaceutically derived medications or other non-herbal substances,4 which should be taken into consideration before jumping to conclusions. This helps separate what one study4 aptly termed true ‘interaction from overreaction’.
Table 37.1 Comparison of the evidence from studies of herb–drug interactions
| STUDY DESIGN | ADVANTAGES | DISADVANTAGES |
|---|---|---|
| Controlled clinical trial in patients |
Source: Coxeter PD, McLachlan AJ, Duke CC, Roufogalis BD. Herb–drug interactions: an evidence based approach. Current Medicinal Chemistry 2004;11:1513–1525.
With conclusive evidence to substantiate drug–herb interactions often lacking, it is usually the clinician that is left to speculate on a potential interaction between a herb and a drug.4 Current academics in the field of herbal pharmacology suggest that much greater research and funding to assess the clinical significance of drug–herb interactions is required, and that until such a database exists it is wise to closely monitor patients who are elderly, taking multiple medications,4 taking narrow therapeutic index drugs or suffering from serious diseases, conditions or disorders.
APPROACHING PATIENTS ON MEDICATIONS
Dealing with patients taking medications is one of the most challenging areas of complementary medicine practice, especially where polypharmacy is concerned.9 A methodical and systematic approach (the INQUIRE method) to prescribing complementary medicines to patients taking pharmaceutical medications is proposed by this author as being best practice (see the box below). The method was designed specifically for students of herbal and naturopathic medicine to reduce the potential for oversight and to implement foundational skills that can be honed while under supervision. The INQUIRE method is discussed in more detail below.
Investigate: All medications must be suitably researched and investigated to provide a rational foundation to identify potential interactions using appropriate pharmacological resources (e.g. MIMS). This allows the naturopath to be cognisant of
particularly problematic medications and therefore assists the selection of appropriate CAM therapies. Should the naturopath still be uncertain or need clarification, they should contact their local pharmacist for an expert opinion. Pertinent questions include:
QUICK GUIDE TO MEDICAL PRESCRIBING TERMS
q.d.: every day (quaque die, once daily)
b.i.d.: twice daily (bis in die)
t.d.s.: to be taken three times a day—used for oral medications (ter die sumendus)
t.i.d.: thrice daily—used for external medications (ter in die)
q.i.d.: four times daily (quater in die)
PAIN MANAGEMENT
Pain is a disagreeable subjective physiological and psychosocial experience that often serves a biological purpose (warning of injury).18–20 It incorporates both the perception of a painful stimulus and the response to the aforementioned perception.21 Physiologically, it can be classified into either somatogenic (organic) or psychogenic (non-organic) origin.22 Somatogenic pain occurs as a result of a direct physiological mechanism or insult (such as osteoarthritis) and can be further divided into nociceptive pain (for example, ongoing activation of visceral nociceptors) or neuropathic pain (neurological dysfunction such as nerve compression).22 Pain can further be explained by duration of effect, being either acute (lasting less than 4 weeks) or chronic (pain lasting longer than 12 weeks).
Further compounding the deleterious physiological effects of pain are social, emotional and psychological23 ramifications, which are especially prevalent in chronic pain, causing debilitating sequelae such as affective disorders and comorbid depression.22 Factors such as age, gender, race and socioeconomic status are also important to consider in pain perception.24 Pain sufferers are often impaired in their ability to initiate or maintain fundamental daily activities such as eating, shopping and cleaning,25 further isolating the patient and increasing morbidity scales (decreasing quality of life).
The perception of pain is physiologically mediated mainly by myelinated A-delta (Aδ) fibre and unmyelinated C-fibre terminal nerve endings, in combination with the neurotransmitter glutamate.18,24 In response to mechanical stimuli and subsequent chemical release at the site of injury, these nerve endings increase firing rates and cause pain by either direct stimulation or sensitising nerve endings.18 Both A-delta and C-fibres transmit electrical impulses from the peripheral nervous supply through the dorsal root and into the dorsal horn of the spinal cord.24 Myelination causes the A-delta fibres to transmit impulses extremely quickly, compared to the slower travelling unmyelinated C-fibres. Acute and sharp pain travels via the A-delta fibres in contrast to the more chronic, dull pain generally associated with C-fibre transmission.18 Other fibres, such as silent nociceptors and A-beta fibres, occur in joints and the periosteum, and can also augment the pain response.26
Our physiological understanding of the source of pain, especially in osteoarthritis, is not well understood,24
