The publication impact of analgesics classified as novel is presented in Table 6. It demonstrates that the highest number of all publications among these drugs belongs to triptans: 1160 articles on sumatriptan plus 791 articles on 6 other triptans. Figure 3A illustrates how the modification of serotonin receptor agonists (the development of sumatriptan and other triptans) changed (starting in 1990–1994) the share of pain publications focused on serotonin. This increase was especially pronounced with RCTs. The publications related only to triptans are presented in Figure 3, B and C (all articles and RCT articles, respectively). The figures demonstrate that the publications on sumatriptan appeared 5 to 7 years earlier than on other triptans. It is interesting that RCT publications on sumatriptan only (excluding other triptans) profoundly decreased after 2006 (Fig. 3C). The other group of drugs in this category, COX-2 selective inhibitors, has significantly fewer publications than triptans (306 articles on celecoxib plus 570 on 2 other drugs from this group) (Table 6). The increase of the publications on the cardiovascular risk of COX-2 inhibitors and the related withdrawal of rofecoxib and valdecoxib from the market are presented in Figure 4. Opioid agonist-antagonists have a number of all publications close to that of COX-2 inhibitors, although the period of publication is much longer with the former (45 vs 12 years).
Among the drugs with novel molecular targets (Table 6), ketamine has the highest number of publications: 1195 for all articles and 330 for RCT articles. These numbers are several times higher than those of 3 other drugs in this category of novelty. Ketamine has a very large time span of publications from 1968 to 2009; however, the reliable confirmation of its effectiveness in pain relief came relatively recently and is related to the treatment of postoperative pain.21 It is obvious that the publication impact of drugs with the real novelty of a defined molecular target is less than that of many other drugs characterized only by incremental improvement on existing drug mechanisms. Table 7 presents the publication impact of analgesics only for the 2000 to 2009 period and it is limited to drugs with the highest levels of the impact (a share of 0.02% or higher for all articles or 1% or higher for RCT articles determined by using total number of pain-related publications in these categories). It is interesting that among drugs with novel molecular targets of action, only ketamine, sumatriptan, and celecoxib reached the level we set for inclusion in this table; however, they were not with the most significant impact. For example, sumatriptan had fewer publications than fentanyl or indomethacin.
Among non-opioid and non-NSAIDs, gabapentin (initially suggested as an anticonvulsant) has the largest number of pain-related publications. It is interesting to note that gabapentin has a publication impact feature common to a number of other new analgesics: at their introduction, the share of RCT articles devoted to them increased to a greater degree than the share of all types of articles (Fig. 5).
Table 8 presents publications on pharmacological modulators of pain in the period 2000 to 2009. New drugs for the treatment of pain may be expected to emerge from among compounds acting on the molecular targets related to these modulators. The number of all articles reflects the intensity of general research activity associated with a specific modulator(s). The number of RCT articles indicates activity quite close to the development of a specific drug(s). The highest level of activity is related to the following modulators: glutamate, cytokines, protein kinases, adenosine, and cholinergic modulators. It is interesting that during the same time period (2000–2009), pain publications on morphine alone were many times more numerous (Table 7) than publications on any of the pain modulators studied for the past decade.
As stated above, of 59 drugs developed from 1960 to 2009 and presently in use for the treatment of pain, 39 were specifically developed for this purpose, and 20 were developed for nonpain indications, but their effectiveness in pain was later confirmed by meta-analysis or by FDA approval for the treatment of pain. With a few exceptions (7 of 59), the molecular targets of their actions underlying analgesia are not novel. Hill2 suggested the division of new analgesics into 3 main classes according to the degree to which their development represents a real advance: (1) an incremental improvement on an existing drug mechanism; (2) novel selective mechanism arising from a better understanding of the mechanism of an existing analgesic; and (3) completely novel mechanism. Only drugs presented in Tables 3 and 4 can be regarded as having novel molecular targets that determine their analgesic effect. This review identifies only 3 drugs (Table 3)—pentazocine, sumatriptan, and celecoxib developed on the basis of a modified molecular target arising from existing analgesics but with an important modification. Capsaicin (topical), ziconotide, ketamine, and dronabinol were identified (Table 4) as drugs with completely novel molecular targets. With the exception of ziconotide, these drugs were known for a long period of time, although the novelty of their molecular targets was discovered relatively recently.
The novelty characterizing the molecular targets of the above drugs does not necessarily determine the degree to which their introduction represents a therapeutic advance. Clinical effectiveness is the final determining factor of a drug's success. For example, sumatriptan's effectiveness is superior to that of any of the 4 drugs in Table 4 with a higher degree of molecular target novelty. An effective novel drug usually has a drug “following.” The number of similar drugs acting on the same target that emerge after a breakthrough drug can indicate its clinical success. The introduction of sumatriptan was followed by the introduction of 6 other triptans. In contrast, so far, none of the drugs in Table 4 have an impressive “following” with the same molecular target. At the same time, the clinical effectiveness of sumatriptan is far from outstanding; it provided complete pain relief in only one-third of patients with acute migraine (and partial pain relief in two-thirds).17 There was no convincing evidence that the difference in effectiveness between the treatments based on NSAIDs and sumatriptan is statistically significant.18,19 This can be explained by the relatively small advantage of sumatriptan over NSAIDs (aspirin). According to McQuay and Moore,23 a close approximation to the true clinical impact of an analgesic therapy requires an extremely large number of patients per group, making it very difficult to establish even a moderate advantage of one analgesic over another.
Publication productivity in the area of pain for the 1960 to 2009 period grew exponentially. The number of articles almost tripled during the first and second decades then doubled during each of the next 3 decades for all categories of articles. Pain-related publications on opioids and NSAIDs were dominant among publications on analgesics. The dominance of publications on opioids is best illustrated by pain-related publications in the 2000 to 2009 period on morphine and fentanyl, 5786 and 2153, respectively. This can be compared with only 796 publications on sumatriptan and 817 on ketamine (2 drugs with the highest publication impact among analgesics with novel molecular targets). The dominance of publications on opioids and NSAIDs reflects their position as the mainstay in clinical practice.
One of the most important categories of articles reflecting clinical research is the RCT, because it provides a higher quality of evidence than other types of clinical articles. When a drug is in the process of introduction into clinical practice, the share of RCT articles about it usually increases to a greater degree than the combined share of all other types of articles about this analgesic. Figures 3A and 5 illustrate this feature of the publication impact of a new analgesic.
The distribution of publications among different analgesics demonstrating that the lion's share belongs to morphine could be interpreted as evidence of insufficient progress in the development of new analgesics. The number of articles about morphine expressed as a percent of all pain publications was approximately 4% both in the 1970 to 1989 and in the 1990 to 2009 period; a 20-year difference did not shift the interest from morphine to new developments. For all opioids, the percent of publications was 6.6% for 1970 to 1989 and 7.5% for 1990 to 2009; for NSAIDs it was 3.7% for 1970 to 1989 and 3.9% for 1990 to 2009. This does not indicate that the number of articles related to drugs for the treatment of pain is relatively stable in general. For comparison, the profound decrease in pain publications on β-blockers can be considered. For the same time periods, it decreased from 3% to 0.5%. The dominance of publications on morphine is especially indicative of insufficient progress in the development of new analgesics, because it persists even in areas where the effectiveness of opioids is rather low, for example, in the treatment of neuropathic pain. The ≥50% NNT index of opioid effectiveness in neuropathic pain is approximately 2.5.24 This means that only 1 of 2 or 3 patients will achieve pain relief and this relief will be only partial. The limited analgesic effectiveness demonstrates that the current clinical practice based on morphine leaves a great deal of room for more effective analgesics. Anticonvulsives and antidepressants frequently used for the treatment of neuropathic pain have NNT values similar to opioids.23,24 Nevertheless, there has been no major improvement in this area.
The major limitation of the publication metrics used is associated with uncertainty regarding the effect of extensiveness of drug use on the number of publications. Prevalence of analgesic prescribing for NSAIDs and opioids25 seems to correlate with their dominance in research articles. However, it is possible that the publication volume of a new and very effective drug might cut significantly into the morphine and NSAID volume.
Research leading to the development of new analgesics and directed at various molecular targets related to pain mechanisms produced thousands of new publications (Table 8). Merely the diversity of molecular targets demonstrated by the table indicates that our understanding of clinical pain mechanisms is still limited; this is probably the main reason for the limited success in the development of new analgesics.
The demonstrated paucity of novel analgesics is difficult to explain. Pain mechanisms that are not yet discovered or mechanisms that are already known but not appropriately used for drug development could be the root of the problem. However, 3 factors contributing to the apparent drought of novel analgesics can be suggested: (1) insufficient mechanism-based approach to clinical pain syndromes, (2) inadequate predictive validity of animal models for pain in humans, and (3) absence of the comparative benefit requirement for the approval of a new analgesic.
The need for a mechanism-based classification for clinical syndromes was stated by Woolf et al.26 in the hope that it might generate testable hypotheses for the development of new treatments that act via specific mechanisms. Many attempts for the past 10 years demonstrated that associating particular clinical symptoms and signs with the underlying mechanisms that may reveal potential targets for pharmacological intervention is a very difficult task. A promising step in this regard was reported for low back pain.27
The other factor that hinders discovery of truly new analgesics is inadequate predictive validity of animal models for pain in humans. Failures in this regard have been related to both adverse effects and lack of efficacy of drugs in humans that seemed to be safe and effective in animal models.1 This problem is so significant that some have called for abandonment of animal pain studies in favor of more extensive testing in humans.28
The third factor is related to the FDA requirements for the approval of a new analgesic. The FDA requires developers of new drugs to demonstrate the drug's safety and effectiveness to receive approval for market entry. Usually, drugs are approved on the basis of demonstrated superiority to placebo, not on the basis of superiority to an active comparator,29 which contributes to the development of “me too drugs.” Placebo-controlled trials require smaller sample sizes than active-comparator trials and therefore are less expensive (they also present less risk of unanticipated adverse effects). Without the requirement for active-comparator superiority trials, it is possible to direct the development of new drugs to research providing a greater return on investment than research aimed at true clinical innovation.
In conclusion, 59 drugs identified as analgesics were introduced from 1960 to 2009 and remain in use. Seven can be regarded as having novel molecular targets; however, only one, sumatriptan, was sufficiently effective to motivate the introduction of many similar drugs acting at the same target (triptans). Publication productivity in the area of pain grew exponentially; the number of articles almost tripled during the first and second decades of the period 1960 to 2009 and then doubled during each of the next 3 decades. Pain-related publications on morphine were dominant among other analgesics even during the most recent years. Very intensive research efforts directed at diverse molecular targets related to pain mechanisms produced thousands of publications, but those efforts have not yet yielded new analgesics with sufficient effectiveness to significantly change the share of publications about opioids or NSAIDs. Morphine and aspirin, introduced for the treatment of pain more than a century ago, continue to dominate biomedical publications despite their limited effectiveness in many areas (e.g., neuropathic pain) and multiple serious adverse effects.
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