Scientometrics of drug discovery efforts: pain-related molecular targets

Figures & data

Table 1 Keywords used for searches related to pain modulators and their molecular targets

Number	Topic	Keywordsa used in addition to “pain” or “pain and migraine”
1	Purinergic receptors	Purinergic receptors, adenosine receptors, A1, A2, A3, P2Y, P2X
2	Serotoninb	Serotonin
3	Bradykinin	Bradykinin
4	Substance P	Substance P, NK-1
5	TRP channels	Transient receptor potential channels, TRPV1, TRPA1, capsaicin
6	Calcium channels	Calcium channels, T-type, N-type, CaV2.2, CaV3.2
7	Cholecystokinin	Cholecystokinin
8	Cytokines	Cytokines, chemokine, TNF-α, IL-1β
9	GABAb	GABA, gabapentin, pregabalin
10	Glutamateb	Excitatory amino acid agonists, glutamate, AMPA, NMDA, kainate
11	Botulinum toxinsb	Botulinum toxins, Botox
12	Cannabinoids	Cannabinoids, CB1, CB2
13	CGRPb	Calcitonin gene-related peptide, CGRP, RAMP1
14	Neurotrophins	Nerve growth factors, BDNF, GDNF, TrkA
15	Nitric oxide synthaseb	Nitric oxide synthase, iNOS
16	Protein kinases	Protein kinases, PKA, PKC, MAPK, ERK
17	VGSC	Voltage-gated sodium channels, NAV1.3, NAV1.7, NAV1.8

Notes:

a A keyword was included if its addition increased the total number of articles by ≥2%;

b topic was searched with “migraine” added to “pain” term. As a result, the popularity index of a topic marked by “b” can be slightly lower compared with popularity of a topic not marked by “b”, despite the similar number of articles for these two topics.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Table 2 General scientometric data on topics related to pain modulators and their molecular targets

Number	Topic	Initial 5-year perioda	Number of articles			Number of patents			Drugs approved by FDA for pain relief
			2004–2008	2009–2013	Total of all 5-year periods	2004–2008	2009–2013	Total of all 5-year periods
1	Purinergic receptors	1984–1988	549	1,120	2,354	14	0	39
2	Serotonin	1984–1988	1,608	1,555	6,241	21	11	135	Sumatriptan (92), zolmitriptan (97), naratriptan (98), rizatriptan (98), almotriptan (01), frovatriptan (01), eletriptan (02), duloxetine (06), milnacipran (09)
3	Bradykinin	1989–1993	252	208	943	9	11	42
4	Substance P	1989–1993	514	481	2,097	3	1	35
5	TRP channels	1989–1993	1,187	1,722	4,000	17	14	60	Capsaicin, 8% patch (09)
6	Calcium channels	1994–1998	595	777	1,722	29	10	76	Ziconotide (04)
7	Cholecystokinin	1994–1998	108	79	438	1	0	2
8	Cytokines	1994–1998	2,066	3,410	7,186	11	2	33
9	GABA	1994–1998	1,335	1,945	4,263	5	8	30	Gabapentin (02), pregabalin (09), gabapentin enacarbil (12), valproate (14)
10	Glutamate	1994–1998	1,517	1,532	4,489	26	21	130	Ketamine (confirmed in CR, 06)b
11	Botulinum toxins	1999–2003	505	622	1,389	22	13	65
12	Cannabinoids	1999–2003	557	651	1,473	18	17	48	Dronabinol (confirmed in CR, 07)b
13	CGRP	1999–2003	526	760	1,589	54	31	88
14	Neurotrophins	1999–2003	426	674	1,405	15	13	30
15	Nitric oxide synthase	1999–2003	329	462	1,040	11	5	36
16	Protein kinases	1999–2003	869	1,525	2,773	5	12	27
17	VGSC	2004–2008	267	422	689	7	9	16

Notes:

a Period when the number of articles and patents were ≥300 or ≥3, respectively;

b effectiveness in pain confirmed by meta-analysis, see in Bell et al²¹ and Iskedjian et al.²⁸

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; FDA, US Food and Drug Administration; VGSC, voltage-gated sodium channels; CR, Cochrane review.

Table 3 Article-related index of change for topics on pain modulators and their molecular targets

Number	Topic	Index of change
		1984–1988	1989–1993	1994–1998	1999–2003	2004–2008	2009–2013
1	Purinergic receptors	>100a	48	95	86	61	>100
2	Serotonin	36	67	65	83	10	−3
3	Bradykinin	12	92	13	54	16	−17
4	Substance P	77	59	21	28	13	−6
5	TRP channels	46	>100	78	>100	96	45
6	Calcium channels	–	>100	>100	>100	>100	30
7	Cholecystokinin	>100	15	32	33	−24	−27
8	Cytokines	>100	>100	>100	>100	79	65
9	GABA	87	43	>100	>100	91	46
10	Glutamate	>100	>100	>100	84	62	1
11	Botulinum toxins	–	>100	>100	>100	93	23
12	Cannabinoids	–	>100	>100	>100	>100	17
13	CGRP	–	>100	63	81	74	44
14	Neurotrophins	–	–	>100	>100	39	58
15	Nitric oxide synthase	–	–	>100	82	32	40
16	Protein kinases	–	>100	>100	>100	>100	75
17	VGSC	–	–	–	>100	>100	58

Notes: Article-related index of change is the percentage change in number of published articles on a specific topic during a 5-year period compared with the previous similar period;

a >100, indicates more than 100%.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Table 4 Article-related index of popularity for topics on pain modulators and their molecular targets

Number	Topic	Index of popularity
		1984–1988	1989–1993	1994–1998	1999–2003	2004–2008	2009–2013
1	Purinergic receptors	0.3	0.3	0.4	0.5	0.6	0.8
2	Serotonin	1.1	1.4	1.6	2.0	1.6	1.0
3	Bradykinin	0.2	0.4	0.3	0.3	0.2	0.1
4	Substance P	0.7	0.8	0.7	0.7	0.5	0.3
5	TRP channels	0.3	0.5	0.6	0.9	1.2	1.2
6	Calcium channels	<0.1	0.1	0.2	0.4	0.6	0.5
7	Cholecystokinin	0.3	0.2	0.2	0.2	0.1	<0.1
8	Cytokines	0.3	0.7	1.2	1.7	2.0	2.4
9	GABA	0.3	0.3	0.6	1.0	1.3	1.3
10	Glutamate	0.2	0.5	1.0	1.3	1.5	1.0
11	Botulinum toxins	<0.1	<0.1	0.1	0.4	0.5	0.4
12	Cannabinoids	–	–	0.1	0.4	0.6	0.5
13	CGRP	0.1	0.3	0.3	0.4	0.4	0.5
14	Neurotrophins	–	–	0.3	0.4	0.4	0.5
15	Nitric oxide synthase	–	–	0.3	0.4	0.3	0.3
16	Protein kinases	–	0.1	0.2	0.6	0.9	1.1
17	VGSC	–	–	–	0.1	0.3	0.3

Notes: Article-related index of popularity is the percentage of published articles on a specific topic among all articles on pain published over the same 5-year period.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Table 5 Index of expectations for topics on pain modulators and their molecular targets

Number	Topic	Index of expectations
		1984–1988	1989–1993	1994–1998	1999–2003	2004–2008	2009–2013
1	Purinergic receptors	6.0	9.6	10.4	15.2	11.6	6.1
2	Serotonin	12.8	14.7	6.7	7.2	5.9	6.2
3	Bradykinin	16.9	9.6	12.8	16.1	16.7	13.0
4	Substance P	11.4	15.3	14.4	14.7	8.0	9.4
5	TRP channels	19.4	22.3	25.0	22.4	16.8	12.0
6	Calcium channels	–	14.3	19.3	16.3	13.3	12.0
7	Cholecystokinin	9.9	9.8	13.9	10.5	5.5	11.3
8	Cytokines	–	2.8	5.5	5.5	6.2	4.5
9	GABA	14.3	13.2	14.8	17.4	10.9	8.6
10	Glutamate	15.2	23.8	23.3	18.9	12.3	11.4
11	Botulinum toxins	–	–	–	5.0	4.2	2.9
12	Cannabinoids	–	–	18.3	18.9	16.5	13.5
13	CGRP	–	–	7.2	12.2	11.6	9.5
14	Neurotrophins	–	–	13.1	13.8	8.9	8.9
15	Nitric oxide synthase	–	–	18.7	11.2	9.4	5.8
16	Protein kinases	–	–	10.5	10.8	11.5	8.4
17	VGSC	–	–	–	9.3	16.5	12.3

Note: Index of expectations, ie, the Top Journal Selectivity Index, is the ratio of the number of articles on a particular topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals on the same topic covered by PubMed over 5 years.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Table 6 Number of articles on investigational drugs with pain-related results (2009–2013)

Number	Topic	Pain was primary aim of trial			Pain was not primary aim of trial, but pain-related results were reported
		Phase I–IIa	Phase IIIa	Total	Phase I–IIa	Phase IIIa	Total
1	Purinergic receptors	0	0	–	10	6	16
2	Serotonin	7	5	12	6	3	9
3	Bradykinin	0	0	–	0	0	–
4	Substance P	0	0	–	2	0	2
5	TRP channels	3	1	4	0	0	–
6	Calcium channels	0	0	–	1	1	2
7	Cholecystokinin	0	0	–	1	0	1
8	Cytokines	1	1	2	60	16	76
9	GABA	4	13	17	1	1	2
10	Glutamate	0	0	–	5	3	8
11	Botulinum toxins	2	9	11	1	2	3
12	Cannabinoids	1	0	1	1	1	2
13	CGRP	3	2	5	0	0	–
14	Neurotrophins	1	0	1	1	0	1
15	Nitric oxide synthase	0	0	–	0	1	1
16	Protein kinases	0	3	3	60	9	69
17	VGSC	0	0	–	0	0	–

Note:

a Phases of clinical trials required for marketing of new drugs.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Table 7 Balance between Phase I–II trials and Phase III trials in the area of investigational drugs for pain relief (2009–2013)

	Area	Number of articles		TBIa (I–II/III ratio)
		Phase I–II	Phase III
Drugs designed for pain relief	GABA	4b	13b	0.3
	Serotonin	7b	5b	1.4
Some other types of drugsc	Cytokines	1,070	303	3.5
	Protein kinases	1,233	256	4.8

Notes:

a TBI is the ratio of the number of articles representing the Phase I plus the Phase II trials of investigational drugs on a topic to the number of articles representing the Phase III trials on the same topic;

b only articles when pain was a primary aim of a trial;

c not necessarily related to pain.

Abbreviations: GABA, gamma aminobutyric acid; TBI, trial balance index.

Table 8 Patent-related index of popularity for topics on pain modulators and their molecular targets

Number	Topic	Index of popularity
		1984–1988	1989–1993	1994–1998	1999–2003	2004–2008	2009–2013
1	Purinergic receptors	–	–	0.5	1.0	0.9	–
2	Serotonin	1.4	2.8	3.6	2.2	1.3	0.9
3	Bradykinin	–	0.7	0.5	0.8	0.6	1.0
4	Substance P	–	0.9	1.6	0.7	0.2	0.1
5	TRP channels	0.3	1.1	1.3	0.7	1.1	1.2
6	Calcium channels	–	0.5	1.8	1.1	2.0	0.9
7	Cholecystokinin	–	0.5	0.1	–	0.1	–
8	Cytokines	–	–	0.3	1.0	0.7	0.2
9	GABA	–	–	0.2	0.8	0.3	0.6
10	Glutamate	–	–	2.4	3.4	1.3	1.6
11	Botulinum toxins	–	–	–	1.7	1.3	1.0
12	Cannabinoids	–	–	–	0.8	1.2	1.5
13	CGRP	–	–	–	0.2	3.3	2.5
14	Neurotrophins	–	–	–	0.1	1.0	1.1
15	Nitric oxide synthase	–	–	0.4	1.1	0.7	0.4
16	Protein kinases	–	–	–	0.6	0.3	1.0
17	VGSC	–	–	–	–	0.5	0.8

Note: Patent-related index of popularity is the percentage of US patents on a specific topic among all other US patents on pain published over the same 5-year period.

Abbreviations: TRP, transient receptor potential; GABA, gamma aminobutyric acid; CGRP, calcitonin gene-related peptide; VGSC, voltage-gated sodium channels.

Figure 1 Time courses of popularity indices related to patents and articles for TRP channels (A) and serotonin (B).

Notes: The article-related popularity index is the percentage of articles on a topic among all articles on pain published over the same 5-year period. Similarly, the patent-related popularity index is the percentage of patents on a topic among all US patents pertinent to pain. The figure indicates that changes in the patent-related popularity index on these two topics occur faster than for the article-related popularity index.
Abbreviation: TRP, transient receptor potential.

BellRFDahlJBMooreRAKalsoEPerioperative ketamine for acute postoperative painCochrane Database Syst Rev20061CD00460316437490

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