Analgesic Combinations as a Strategy for Pain Relief and Isobolographic Analysis

Arlette Guadalupe Arroyo-Lira, Aracely Evangelina Chávez-Piña

Abstract

Pain is a multidimensional sensory experience that is intrinsically unpleasant and associated with hurting and soreness, it is essentially a sensation. Pain has strong, cognitive and emotional components, it is linked to, or described in terms of suffering. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and opioid analgesics are two of the most common types of drugs used for pain management. However, the use of these analgesics is limited by the presence of significant adverse effects. A useful practice is a combination of two agents with the same therapeutic effect wherein each agent is administered to obtain additive, synergistic or subadditive interaction in a fixed ratio. If the combination resulted in addition or synergism, the doses employed by each agent are reduced, then the side effects are absent; this kind of study is named isobolographic analysis. In this review, the authors summarized previous reports of the combination of NSAIDs with opioids and natural products as an alternative in the pain management.

Keywords: analgesic, combination, interaction, isobolographic analysis, nsaids, opioids

Introduction

Almost everybody will probably suffer from pain during a period of their lives¹. Pain is defined by the International Society for the Study of Pain (IASP)² as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. Pain represents the first cause of medical consultation³. For example, in industrialized countries, chronic pain is a major public health concern due to the high cost of medical treatment and the loss of productivity in the workplace⁴, it exerts tremendous socioeconomic costs, exceeding $100 billion USD annually². Pain relief can be achieved by a diversity of methods, being drug use the basis of analgesic treatment⁵. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and opioid analgesics are two of the most common types of drugs used for pain management⁶. However, the use of these analgesics is limited by the presence of significant side effects; for example, it is well known that gastric damage is the major NSAID-induced side effect⁷, and opioids are frequently accompanied by many side effects such as bradycardia, hypothermia, urinary retention, respiratory depression, physical dependence, constipation, sedation and tolerance⁸. On other hand, the use of natural agents for pain relief is currently a common practice.

In order to diminish the side effects, the use of analgesic combinations of proven efficacy is a strategy intended to achieve one or more therapeutic goals; for example, improving efficacy without increasing adverse effects or decreasing adverse effects without losing efficacy ⁹. With polypharmacy and an increase in the number of people taking alternative therapies, it is important to know the kind of drug interaction. An important tool is the method of isobolographic analysis.

Pain and its management

Pain can be defined simply as the subjective experience of harm in a part of one´s body¹⁰. While in the past pain was seen as a relatively simple symptom, it is becoming increasingly clear from the molecular-biological mechanisms to the impact on social systems, it is in fact, a highly complex phenomenon¹. However, in reality, there are multiple forms of pain, which involve a variety of distinct biological processes. Exposure to extreme heat, cold or pressure can be noxious,  and  trigger nociceptive pain. Inflammatory pain, involving the release of cytokines and the infiltration of immune cells, also occurs subsequently in injuries, but can be triggered independently by bacterial infections¹⁰. Although, pain has an important physiological role in preserving the integrity of the body, pathological pain also exists. For instance, nerve damage in surgery patients sometimes leads to chronic pain conditions that can last years or even decades¹⁰. An important factor to consider in the evaluation and pain management is a high variable experience among individuals². Many different types of drugs serve as an effective complement to NSAIDs or opioids in pain management¹¹. The World Health Organization (WHO) has developed a three-step “ladder” for pain relief, generally involving matching the degree of pain with the analgesic category, named NSAIDs for Step 1 (‘weak’) pain and opioids for Step 3 (‘severe’) pain^{12, 13}.

Analgesic Combinations:

In general, a combination therapy or multi-target approach is understood as a combination of two or more active pharmaceutical ingredients with complementary mechanisms of action, which extends a range of therapeutic options in the treatment of almost every human disease. In many important therapeutic areas such as diabetes, infectious disease, asthma, hypertension, depression, anxiety disorder, and as discussed here, pain therapy and multi-component drugs are now standard. Drugs directed at individual targets are often found to be less effective in treating disease or disease symptoms than multi-target therapeutics, which applies particularly in the case of pain therapy¹, ¹⁴ . The practice of combining drugs in pain management is based mainly on two considerations. Firstly, a network of brain areas is involved in pain perception and pain control; single drugs do not always provide satisfactory pain relief: combining drugs which act on different receptors and different pain mechanisms may enhance pain relief. Secondly, single drugs which provide satisfactory pain relief may cause, at the same time, unacceptable side effects¹.

Currently, pain is generally treated with opioids, NSAIDs, antidepressants, and anticonvulsants, but negative side effects remain¹⁵.  Because of the side effects of drug profiles, there is a greater interest in combining compounds. For example, an agonistic acting at α2-adrenergic receptors such as clonidine and an opioid like morphine showed antinociceptive synergistic interactions, but not in the sedative/motor or cardiovascular side effects, these data support the utility of combining adrenergic/opioid therapy in pain management for antinociceptive efficacy with reduced side effects¹⁶. Furthermore, another opioid such as tramadol exhibited antinociceptive synergistic interaction when it was combined with ibuprofen (a non-selective NSAID) ¹⁷ and ursolic acid, a triterpene isolated from herbal medicines to treat pain¹⁸. However, not always the interaction with two agents which individually induce antinociceptive effects is synergistic or additive; opioids do not seem to potentiate analgesic effects of selective COX-2 inhibitors, in contrast to nonselective COX inhibitors, for example, three combinations of rofecoxib plus tramadol presented high sub-additive interactions, besides, rofecoxib (17.8 mg/kg) and tramadol (10.0 mg/kg) combination caused more severe gastric injuries than those obtained with rofecoxib or tramadol during single administration¹⁹. In addition, codeine did not increase the antinociceptive efficacy of coxibs, when codeine was combined with etoricoxib showed sub-additive effect and with celecoxib, it exhibited just additive interaction, while with non-selective NSAIDs such as ibuprofen, it induced synergistic effect²⁰.  Furthermore, glucosamine combined with different non-selective NSAIDs resulted in synergism with ibuprofen and ketoprofen, in addition with diclofenac, indomethacin, naproxen and piroxicam and sub-additive aspirin and acetaminophen antinociceptive interaction²¹.

There are several reports of the possible interactions between natural agents such as dietary supplements and herbal remedies, which have been used for centuries to reduce pain and inflammation²².  The interaction between fish oil and paracetamol for inhibition of prostaglandin synthesis in patients with rheumatoid arthritis (RA) has been evaluated. Combining paracetamol with fish oil the nociceptive inhibition of PGE2 synthesis appears to be achievable in patients with RA²³. On other hand, a synergistic interaction between Heliopsis longipes (an herbaceous plant found in Mexico) and diclofenac was demonstrated in the Hargreaves model of thermal hyperalgesia in the mouse²⁴. Recently, the systemic antinociception of the combination of citral and naproxen has been confirmed using the isobolographic analysis. In addition, the interaction observed in this combination has fewer gastrointestinal side-effects¹¹.  Besides, ellagic acid (EA), a major constituent of pomegranate juice, induces antinociceptive and anti-inflammatory effect; when EA is combined with venlafaxine (an antidepressant) exhibits synergism in the antinociceptive effect²⁵  but EA combined with carbamazepine just shows additive interaction²⁶  in the same pain model in the rat. Moreover, the combination of rhodiola rosea ethanolic extract with B vitamin (1, 6 and 12) induces synergistic antinociceptive interaction in the mouse formalin test²⁷.

More recently, our group has reported the synergistic antinociceptive and gastric safety effect of the combination of DHA, an n-3 PUFA, an indomethacin, and an NSAID, through an isobolographic analysis²⁸.

Isobolographic analysis

The simultaneous presence of two or more drugs is a common occurrence in clinical settings and in numerous experimental designs aimed to the study of mechanisms. When two drugs (or chemicals) produce overtly similar effects, they are simultaneously presented and it is important to detect and characterize any interaction²⁹. Drug interactions are usually described as pharmacodynamic or pharmacokinetic. Another mechanism of drug interactions is really a pharmaceutical incompatibility³⁰. The pharmacodynamic interactions of the combination of two or more drugs, can be described usually as “additive” when the combination effect is consistent with individual drug potencies, “superadditive” (synergistic), that is, they may demonstrate an action which is above what is expected of their individual potencies and efficacies, while the reduced action is called “subadditive”¹², ³¹

The isobolographic analysis is an important tool that provides a graphical presentation of the nature of a two-drug interaction³². The isobologram starts with a determination of a complete dose-effect data for the individual drugs.²⁹ The potencial and effective information derived from the individual dose-effect curves allows a determination of the expected combination effect or dose combination that produces a specified effect³¹. First, in a two-coordinate plot, one coordinate represents the dose of drug A and the other one represents the dose of drug B; the doses of drugs A and B require to produce a defined x-effect (i.e. ED30). When used as single agents, they are placed on the x and y axes respectively³². This graph commonly contains a straight “line of additivity” (also called isobole) connecting drug A and drug B; the isobole is the locus of points (dose pairs) which will produce the x-effect in a simple additive combination (Zadd). This line of additivity allows a comparison with the actual dose pair that produces the x-effect level experimentally (Zexp). Synergy, additivity, or subadditivity is indicated when the Zexp is located below, on, or above the line, respectively (Fig. 1)³² -35. The pharmacological interaction can differ from a function of the dose ratio administered. In preclinical testing, the most often tested dose ratio is the ratio of the effective dose 50 (ED50) values of the two drugs. A reasonable follow-up is to use 2:1 and 1:2 ratios of the ED50. This choice of dose ratios is symmetrically around the 1:1 ratio and may show additivity or a departure from additivity. Other ratios such as 3:1 and 1:3 might also be tested, thereby scanning the radial sector defined by the axial intercepts is to detect other possible departures from additivity. The different dose ratios may not all be synergistic (or antagonistic), but among those that are synergistic can assess the degree of synergisms from the interaction index (interaction index provides a quantitative measure of the extent of drug interaction at a given effect level)³², ³³, ^35-37 . Although it is useful for its visual display, the isobologram does not obviously allow a statistical distinction³³. At this point, the interaction index is the metrics which allow a distinction made of a statistical analysis about the difference between the total experimental dose (Zexp) and the total additive dose (Zadd). Such analysis is contained in Tallarida (1992) and was furtherly simplified to yield approximate variances for use in a t-test that distinguishes between the total additive and experimental doses.²⁹ In simple words, this method allows to differentiate among “additive”, “synergistic” or “subadditive” interactions (Table 1).

Table 1. This table summarizes some representative drug interaction studies.

Conclusion

Some drug effects are desirable whereas others are undesirable. The ideal situation is one in which the drug combination synergizes the desired effect, but exhibits subadditivity for the undesirable effects. As in the drug combinations in the actuality for pain relief (NSAIDs and opioids) remaining the side-effects, it is important to look for alternative combinations (i.e. NSAIDs plus natural analgesic agents). More important, it is to establish the kind of interactions (additivity, synergistic or subadditivity) in these combinations, and determinate their usefulness.

Acknowledges

The authors acknowledge the support provided by the National Polytechnic Institute (Projects SIP-20150031) and the National Council for Science and Technology (Project CONACyT 178027). Arroyo-Lira Arlette Guadalupe is a CONACyT fellow (Grant Number 269377).

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Author to whom correspondence should be addressed: *Aracely Evangelina Chávez Piña.
Laboratorio de Farmacología
Escuela Nacional de Medicina y Homeopatía
Instituto Politécnico Nacional