7
Complications in the Pharmacologic Approach of Pain

Kris C.P. Vissers MD, PhD, FIPP¹, Priodarshi Roychoudhury MD², and Lakshmi Koyyalagunta MD³

¹ Radboudumc Expertise center for Pain and Palliative Medicine, Nijmegen, The Netherlands
² University of British Columbia, Canada
³ The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Introduction

Complex pain syndromes require multidimensional diagnostic and treatment strategies in order to guarantee the most optimal outcome on pain and quality of life for patients with chronic pain [1, 2]. For decades, the diagnosis and treatment of complex pain syndromes was mostly incomplete as the pathophysiology of chronic pain appears to be far more difficult than the initial view of Descartes. Multidimensional pain strategies focus on non-pharmacologic and pharmacologic approaches often applied concurrently [3, 4]. Optimally, the pharmacologic approach for the treatment of chronic pain is based on a clear mechanism of action within the receptors that are part of the pathophysiologic mechanism involved in chronic pain [5].

In this chapter, we focus on pharmacokinetics and pharmacodynamics of analgesics and the appropriate use of oral, intranasal, transmucosal, transdermal, subcutaneous, intravenous (IV), or subcutaneous and intrathecal analgesics and co-analgesics in strict relation with their indications and contraindications of their use, and when and how to switch toward interventional or non-pharmacologic pain management to avoid these complications [6] (Table 7.1).

Table 7.1 Important messages related to the use of pharmacologic agents for pain.

1) Analgesics should be used in an appropriate way in their prescriptions by prescribers and in use by the patients in order to avoid complications, inadvertent effects and addiction

2) Pharmacologic approach of chronic pain has limitations on the dosage, use, administration route, effect, outcome, and side effect

3) Refractory pain to the pharmacologic approach is not yet well defined and delineated, so not all healthcare professionals (HCP) have good guidelines on when and how to prescribe and when to switch to a non-pharmacologic interventional approach as a pain management strategy

4) Prescribing physicians and pain specialists should have a good knowledge of absorption, metabolization, and excretion of analgesic drugs and develop a more proactive approach to the development of possible side effects and addiction issues in different painful disease trajectories

5) Essential recommendations and evidence-based guidelines should be formulated and implemented to avoid complications of the pharmacologic approach of chronic pain

6) Essential recommendations should be formulated how to switch “on the right moment” from pharmacologic to non-pharmacologic including interventional pain management strategies or how they should be combined to obtain the best possible outcome for patients

Chronic pain is a debilitating disease dramatically affecting the quality of life and functioning of each affected patient [5]. Chronic pain is a condition in its own right and is a greater medical problem than cancer, heart diseases, and diabetes taken together [7]. Over the past 50 years, the diagnosis and management of chronic pain syndromes has evolved from a mere monodisciplinary approach toward a more multi-, inter- and even transdisciplinary approach with many HCP involved and a plethora of pain management options. However, good evidence of all these individual pain treatments is hard to prove for both pharmacologic and non-pharmacologic approaches and requires a more focused and programmed approach globally [8–10].

Each treatment of a patient with chronic pain has its own advantages and disadvantages and often it is still unclear what underlying mechanism makes a positive outcome for a pain treatment. Equally, it is often true for the side effects of the treatment or specific complications. However, it is obvious that difficult treatments in skilled hands cause less damage than in unskilled hands. So, extensive clinical experience and observational capacities to indicate the right treatment in the right patient at the right moment is of upmost importance to guarantee the best possible outcome for a patient and to assure an improvement in the quality of life without losing function or even causing unbearable side effects.

In this book on complications of interventions, we will focus on unwanted effects of pharmacologic pain treatments and how they can be handled or avoided including improving our indications for a specific treatment in a specific condition. Since the outcome of many pain treatments in different conditions is not yet fully clear, a good interaction between the general practitioner (GP) of the individual patient, a medical specialist on a specific condition and a dedicated pain specialist is important to make the appropriate choice of treatment with the highest possible impact on pain relief with the lowest possible side effects or complications. This selection process includes valuable and realistic information about the possible treatment for the patient and an easy understandable informed consent on the procedure, outcome, and possible side effects as well as known complications. In summary, a treatment approach should be tailored for each individual patient.

Pharmacologic Treatment of Pain

In the case of a pharmacologic approach for the treatment of pain, specific basic principles should be respected in all cases.

Selection of the Best Possible Analgesic

First, always select the best possible treatment that best fits the patient and the possible mechanism causing the pain. This principle demands a clear diagnosis of the somatic and psychosocial characteristics of the individual patient and of the pain syndrome such as nociceptive, nociplastic or neuropathic pain related to the location and mechanism of action. Unfortunately, for most of the individual pain syndromes there is insufficient evidence on a first-choice pharmacologic agent resulting in a lot of extrapolation of HCP between individual pain syndromes [11]. More thoroughly symptom-based phenotypical diagnostic evaluation by neurophysiologic tools such as somatic-evoked potentials, quantitative sensorial testing, conditioned pain modulation (CPM), and functional MRI can help close this diagnostic gap in the future [12]. Next, each individual has a different sensitivity to side effects of each individual treatment depending on age, gender, metabolism, and excretion. In some cases, these side effects are positively used in the case of tricyclic anti-depressive agents which cause somnolence giving the patient a good night’s sleep where they are no longer awakened because of pain. Finally, more and more pharmacogenetic counseling, considering the impact of the cytochrome iso enzymes for the metabolization of individual drugs, will impact and improve our choice of the right pharmacologic agent for each individual.

Select the Best Possible Mode of Administration of the Analgesic

Second, always make a selection of the adequate mode of administration for a specific drug. Of course, the administration of any analgesic by mouth is by far the most convenient and commonly used method [13]. However, in the case of a first-pass effect of a specific drug, the analgesic properties can be negatively influenced, or the side effects unpredictable. Often, a transmucosal administration by mouth or nose is chosen to avoid the first-pass effect. Transdermal administration is a slow method giving a stable pharmacologic profile for long-term administration and is easy to use. In most cases, the clinical effect of an analgesic drug administered by the IV, subcutaneous or intramuscular (IM) route results in an equal clinical outcome. However, long-term subcutaneous administration is easier for the home care situation in the case of patients with refractory cancer pain or at the end-of-life care. Finally, the neuraxial administration of a multimodal drug cocktail may be necessary in patients with complex pain syndromes often with a refractory component and when the dosage needed exceeds the tolerance for side effects by other routes of administration. With these administration routes, a specialized hospitalization and homecare nursing team is often necessary to assure the best outcome and an aseptic long-term treatment to avoid infections.

Use Evidence-based Guidelines and Algorithms

Third, always use a clear treatment algorithm such as the World Health Organization pain ladder for cancer pain including the fourth step of invasive pain treatment. Most important, is that the next step of the ladder of the algorithm is taken when the pain treatment modality will not result in a satisfying pain relief for the patient. For non-cancer pain, the pain ladder is not validated, however, in most cases, a clear conservative treatment, such as pharmacologic, physiotherapeutic or psychologic treatment should be given before a more complex interventional treatment modality will be offered.

Use Fixed Dosages Regimens

Finally, always use a fixed-rate dosing regimen with escape medication. In patients with chronic pain, it is useful to use long-acting analgesics that result in a stable plasma level of the analgesic drug. However, it can take longer to achieve a stable plasma concentration for the optimal clinical effect. The easier the administration scheme the higher the therapeutic compliance of the patient and the least side effects due to pharmacologic variations. An important disadvantage is that fluctuations in pain intensity are hard to cover, resulting in breakthrough pain requiring the additional administration of fast-acting analgesics. A close medical monitoring of this therapeutic program is necessary to observe the clinical outcome and to avoid addictive behavior. As the evidence for the long-term administration of opioids in patients with chronic non-cancer pain is weak, a clear indication, and an easily supervised monitoring plan should be conditional for this type of pharmacologic treatment because of the worldwide opioid crisis.

1) Appropriate vs. inappropriate use of analgesics

The appropriate use of analgesics requires patients to receive their medications in relation to their clinical need, in a specific calculated dosage related to their requirements and for a well-monitored period of time that includes a clear periodic evaluation of the clinical outcome and side effects [14] (Table 7.2).

Table 7.2 Examples of irrational use of medicine/analgesics.

Too many medicines per patient (polypharmacy)

Inappropriate use of medications Often inadequate dosages given

Overuse of formulations when oral formulations would be more appropriate

Failure to prescribe in accordance with clinical guidelines

Too much use of prescription-only medications

Inappropriate self-medication

Non-adherence to dosing regimens

So that analgesics are used properly, inclusive evidence-based guidelines based on clinical diagnoses should be developed, implemented, and continuously evaluated on outcome along with possible side effects, complications or addiction. National and international pain and pharmacologic societies should collaborate to guarantee the availability of the best possible knowledge and expertise on analgesic drugs for prescribers, patients and the lay public. Governments and insurance companies should give priority to the availability of essential drugs that have proven efficacy in different clinical pain syndromes. Therefore, the WHO advocates key interventions to promote rational use of medicines.

To ensure the recommendations listed in Table 7.3 are successful, many conditions should be fulfilled. National and international scientific societies should develop an essential drug list for analgesics and related medicines to ensure access and reimbursement. Supervision platforms should be installed to audit, monitor, and evaluate the proper use at individual and societal levels including a focus on early screening, accurate diagnosis to guide analgesic prescriptions and to avoid overuse, underuse, and misuse. Developing evidence-based recommendations, based on clinical diagnoses, should have priority in collaborative initiatives in the national and international societies of pain specialists, pharmacologists, psychiatrists, and GPs supported by epidemiologists to assure the best possible recommendations including algorithms on the diagnosis and (pharmacologic) treatment of pain with the best possible outcome and applicability for patients with the lowest possible side effects and complications. Next, patients should adhere to their treatment by use of shared decision making with pain specialists and their GP, regular evaluation, and monitoring programs by pharmacies and community-based interventions.

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