Wye misspeling drug naims matturs – Jeffrey K Aronson (with Robin E Ferner)

You must misspell drug names when doing a systematic review

1. Introduction

Drug names are difficult to remember, pronounce, and spell.

For example, which of the following is the correct spelling?

• amitriptylin
• amitryptiline
• amitriptylline
• amytriptyline
• amitriptiline

One easy way to find out is to enter the name into PubMed. Here’s what I got when I searched for “amitriptylin”:

The search engine asked me if I meant “amitriptyline”, which is the correct spelling.

But what about those 37 hits that I got by searching for the wrong spelling “amitriptylin”? Well, when I searched for “amitriptylin & amitriptyline” I got the following:

That gave me only 23 hits, compared with the previous 37; 14 hits were missing. And when I searched for “amitriptylin NOT amitriptyline”, there they were:

In other words, unless you searched for the misspelling “amitriptylin” as well as the correct spelling “amitriptyline”, you would miss 14 publications.

In order to determine how many papers you would miss if you didn’t enter misspellings when you search for drug names, Robin Ferner and I searched PubMed systematically for misspellings in 30 drug names that are often misspelled on prescription charts (which we called the test set) and 30 randomly chosen control names. The full findings are published in the BMJ, but here is a summary:

• the 30 standard names of drugs in the test set gave 325,979 hits in total, and 160 misspellings gave 3872 hits that weren’t picked up by the correct spellings;
• the standard names of the control set gave 470,064 hits, and 79 misspellings gave 766 hits that weren’t picked up by the correct spellings;
• letter substitutions (particularly i to y and vice versa) and omissions together accounted for 2924 (74%) of the variants;
• names ending in “in”, “ine”, or “micin” were commonly misspelt;
• failing to search for misspellings of “gentamicin,” “amitriptyline,” “mirtazapine,” and “trazodone” missed at least 19 systematic reviews.

So, if you are doing a systematic review that includes drug names, you’d better include misspellings as well as the proper ones. And you’d better include misspellings of all drug names, not just those that are commonly misspelled.

Here I describe how to generate misspellings for which to search.

 

2. Definitions and how drugs are named

First I need to define some terms:

• Standard names—the international non-proprietary names (INNs), or some other nationally approved name when there is no INN.
• Variant names—deviations in spelling from standard names that are not themselves standard names in English language nomenclatures.
• Hidden reference variants—variant spellings that identify publications in searches of PubMed or other databases, but which are not identified by searches for the standard names.

The box below tells you about International Nonproprietary Names and other types of names that drugs have, but you can skip this if you want.

Some drug naming systems

 

3. How to generate variant spellings

Now I shall describe how to generate variant spellings (i.e. misspellings). There are six basic ways:

• Substitution
• Omission
• Addition
• Transposition (technically known as metathesis)
• Duplication and deduplication
• Combinations of the above

3.1. Substitution

In substitution, one letter is put instead of another. The following are substitutions to look for:

• i instead of y or vice versa [but we have rarely found any examples of a terminal -yde replacing a terminal –ide or a terminal -yne replacing a terminal –ine; epinephryne is an exception, but it yields only one trivial hidden reference];
• an unaccented vowel to another vowel or y;
• soft c to s and vice versa;
• hard c to k and vice versa;
• ch to k;
• f to ph and vice versa;
• ide to ine and vice versa;
• m to n and vice versa;
• th to t and vice versa;
• x to ks.

3.2. Omission

In omission, letters are left out, often just one, sometimes more. The following are omissions to look for:

• the final e in a name ending, for example, in -ide or –ine;
• the letter r.

Other letters are much less often omitted; for example l was omitted from drug names in only 0.03% of cases and x in 0.0009%.

Deduplication is a special form of omission, dealt with below (§3.5).

3.3. Addition

In addition, letters are inserted somewhere in the name. The following are additions to look for:

• an extra e at the end of a name ending in –in;
• an extra letter r;
• an extra letter l.

Duplication is a special form of addition, dealt with below (§3.5).

3.4. Transposition

In transposition (metathesis), two letters or groups of letters are swopped. The following are examples:

• furosemide to fruosemide;
• filgrastim to filgastrim.

3.5. Duplication and deduplication

In duplication a letter is repeated and in deduplication a duplicated letter is reduced to a single letter. The following are changes to look for:

• l to ll and vice versa;
• n to nn and vice versa.

3.6. Combinations

Any of the above changes can be combined in altering any drug name. The following are examples:

• gentamicin to gentamycine (substitution of i by y and addition of a final e);
• amitriptyline to amytriptillin (two substitutions, i to y and y to i, duplication of l, and omission of the final e); the possible combinations of changes in this name yield 31 variants—see next section.

3.6. Examples of how to generate variants systematically

We applied some of these changes to the drug name amitriptyline, as follows:

• we changed each letter i to the letter y and each y to an i, using all possible permutations;
• we looked for duplication of the l;
• we looked for variants without the terminal e;
• we combined all these variants.

We tabulated the results:

Numbers of PubMed hits of hidden reference variant spellings* of the standard name amitriptyline

Variant spellings(i to y substitutions and vice versa)	No of hits
	Spelling with single l			Spelling with double ll
	Without final e	Plus final e		Without final e	Plus final e
i–i–i	8	8		0	0
i–i–y	14	†		1	2
i–y–i	4	80		0	1
i–y–y	1	32		0	1
y–i–i	2	10		0	0
y–i–y	1	10		0	0
y–y–i	0	2		0	0
y–y–y	0	0		0	0
Totals	30	142		1	4

* Included one case of the variant “amitiptyline” lacking the r, and one of “amitriptyine” lacking the l. There was no variant in which the final i was replaced by a y.

† Amitriptyline, the standard name, gave 8530 hits.

3.7. Searching for standard variants

Although it may seem obvious, for the sake of completeness I include here a reminder to search for names that are standard somewhere, and are not in the INN nomenclature. There are two cases:

3.7.1. Names that are different in different nomenclatures

For example, thiomersal is an INN but the USAN is thimerosal. Here are the current data (searching PubMed on 16 December 2016):

Search term	Interpretation	Hits
1. thiomersal[tw]	INN	251
2. thimerosal[tw]	USAN	1700*
3. thiomersal[tw] NOT thimerosal[tw]	INN NOT USAN	123
4. thiomersal[tw] AND thimerosal[tw]	INN AND USAN	128
5. thimerosal[tw] NOT thiomersal[tw]	USAN NOT INN	1572
6. thiomersal[tw] OR thimerosal[tw]	INN OR USAN	1823†

*2 = 4 + 5

†6 = 3+4+5

Thus, there are 1572 hidden reference variants that would not be detected by searching only for the INN. You have to search using both spellings connected by OR.

3.7.2. Drugs that have no INNs

For example, acetylsalicylic acid, also known as aspirin, does not have an INN. Here are the current data (searching PubMed on 16 December 2016

Search term	Hits
1. aspirin[tw]	59452
2. acetylsalicylic acid[tw]	8809*
3. aspirin[tw] NOT acetylsalicylic acid [tw]	53134
4. aspirin[tw] AND acetylsalicylic acid [tw]	6318
5. acetylsalicylic acid [tw] NOT aspirin[tw]	2491
6. aspirin[tw] OR acetylsalicylic acid [tw]	61943†

*2 = 4 + 5

†6 = 3+4+5

Again, you have to search using both spellings connected by OR to find the complete set and also search for misspellings (e.g. asprin, which gives 14 hidden reference variants).

3.8. Searching databases other than PubMed

Other databases pose similar problems to those encountered in PubMed. Here are some notes on Medline.

Medline allows users to search for words that are spelt with alternative letters, using the hash key # as a wild card. For example, a search for “amitriptyline.af.” yields 8092 hits. Searching for “am#tr#pt#line.af.” uncovers variant spellings with i to y substitutions (and vice versa) in amitriptyline, revealing 123 hidden reference variants.

Truncation is also possible. In Medline, truncating amitriptyline at the letter l and using wild cards (“am#tr#pt#l*.af.”) uncovers variants of the last few letters (for example, ending in “-lin,” “-line,” “-llin,” or “-lline”) without sacrificing specificity, and gives further hits.

However, this does not exhaust all variant forms. For example, the hidden reference variant “amitiptyline”, generated by omission of the letter r, was missed. Other errors, such as transpositions and some additions, will also be missed.

The results obtained by truncation may also be limited if an error occurs early in a name. For example, searching for the variant” manitol” instead of “mannitol” yields 58 hidden variants in PubMed and Medline. However, truncating at man* yields far too many hits for a simple analysis, since so many other words begin with ma- (21975 hits in Medline for mannitol and 576489 for mann*).

3.9. Searching for brand names

We have not covered brand names, but this is a reminder to search for those too. For example, searching PubMed for Lasix[tw] NOT (furosemide[tw] OR frusemide[tw]) yields 80 hidden reference variants.

3.10. Examples of variants for which to search

The following table includes variants that we have already found and others that might be found, but which at the time of writing do not have hidden variants. Information about possible additions is welcome.

Standard name (INN)	Variants	Hidden reference variants (16/12/16)
amitriptyline	amitiptyline, amitriptilin, amitriptiline, amitriptillin, amitriptilline, amitriptyine, amitriptylin, amitriptyllin, amitriptylline, amitryptilin, amitryptiline, amitryptillin, amitryptilline, amitryptylin, amitryptyline, amitryptyllin, amitryptylline, amytriptilin, amytriptiline, amytriptillin, amytriptilline, amytriptylin, amytriptylin, amytriptyline, amytriptyline, amytriptyllin, amytriptyllin, amytriptylline, amytriptylline, amytryptilin, amytryptiline, amytryptillin, amytryptilline	178
amoxicillin	amoxicylin, amoxicyline, amoxicyllin, amoxicylline, amoxycilin, amoxyciline, amoxycillin, amoxycilline, amoxycylin, amoxycyline, amoxycyllin, amoxycylline	1166
azathioprine	azathiaprin, azathiaprine, azathioprin, azothiaprine, azothioprin, azothioprine	131
capecitabine	capacitabine, capcitabine, capecitabene, capecitabin, capecitibine	20
carbamazepine	cabamazepine, carbamazapine, carbamazepin, carbamazipine, carbamezepine, carbazepine, carbemazepine	89
ciprofloxacin	ciprafloxacin, ciprofloksacin, ciprofloxacine, ciprofloxacyn, ciprofloxasin, ciprofloxicin, cirpofloxacin, cyprofloxacin	121
clotrimazole	clotimazole, clotrimasole, clotrimazol, clotrimoxazole, cotrimazole, cotrimazole	45
cotrimoxazole	clotimazole, clotrimasole, clotrimazol, clotrimazole, clotrimoxazole, cotrimazole	2719
dipyridamole	dipiridamol, dipiridamole, dipirydamol, dipirydamole, dipyramidol, dipyramidole, dipyridamol, dypiridamol, dypiridamol, dypiridamole, dypirydamol, dypyridamole	144
fidaxomicin	fidaxomycin, fidoxamicin, fidoxamycin	6
filgrastim	filgastrim, filgrastime	20
fosfomycin	fosfomicin, fosfomicine, fosfomycine, fosphomycin, phosfomicin, phosfomicine, phosfomycin, phosfomycine, phosphomicin, phosphomicine, phosphomycin, phosphomycine	80
furosemide	fruosemide, frusamide, frusemide, furosamide, furosemid, furosmide, fursemid, fursemide	46
gentamicin	gentamicine, gentamicyn, gentamycin, gentamycine, gentamycyn, gentimicin, gentimicine, gentimicyn, gentimicyn, gentimycin, gentimycine, gentimycyn	2102
goserelin	gosereline, goserilin, goseriline	10
granisetron	granisetrone, granisteron, granisterone, granysetron, granysetrone, granysteron, granysterone	4
ipratropium	ipatropium, ipratropium, ipetropium, ipretopium, ipitropium, ipritopium	10
lamotrigine	lamotragene, lamotragin, lamotragine, lemotragin, lemotragine, lemotrigin, lemotrigine, lymotragin, lymotragine, lymotrigin, lymotrigine	3
levetiracetam	levatiracetam, levetirecetam, levetirecetame, levetiracetem, levetyracetam, leviteracetam, levitiracetam, levotiracetam	20
mirtazapine	mirtazapin, mirtazepin, mirtazepine, mirtazipin, mirtazipine, mirtazpine, mirtazypin, mirtazypine	35
mycophenolate	mycofenalat, mycofenalate, micofenolat, micofenolate, micophenolat, micophenolate, mycofenolat, mycofenolate, mycophenalat, mycophenalate, mycophenolat, mycophenolate	1
netilmicin	metilmicin, metilmicine, metilmicyn, metilmycin, metilmycine, metilmycyn, metylmicin, metylmicine, metylmicyn, metylmycin, metylmycine, metylmycyn, netilmicine, netilmicyn, netilmycin, netilmycine, netilmycyn, netylmicin, netylmicine, netylmicyn, netylmycin, netylmycine, netylmycyn	60
nortriptyline	nortiptylin, nortiptylin, nortiptyline, nortiptyllin, nortiptyllin, nortiptylline, nortriptilin, nortriptiline, nortriptillin, nortriptilline, nortriptylin, nortriptylin, nortriptyllin, nortriptylline, nortryptilin, nortryptiline, nortryptillin, nortryptilline, nortryptylin, nortryptyline, nortryptyllin, nortryptylline, notiptylin, notiptyline, notiptyllin, notiptylline, notriptylin, notriptylin, notriptyline, notriptyllin, notriptyllin, notriptylline	38
opioid	opiod, opoid	65
pentoxifylline	pentoxifilin, pentoxifiline, pentoxifillin, pentoxifilline, pentoxifylin, pentoxifyline, pentoxifyllin, pentoxiphilin, pentoxiphiline, pentoxiphillin, pentoxiphilline, pentoxiphylin, pentoxiphyline, pentoxiphyllin, pentoxiphylline, pentoxyfilin, pentoxyfiline, pentoxyfillin, pentoxyfilline, pentoxyfylin, pentoxyfyline, pentoxyfyllin, pentoxyfylline, pentoxyphilin, pentoxyphiline, pentoxyphillin, pentoxyphilline, pentoxyphylin, pentoxyphyline, pentoxyphyllin, pentoxyphylline	192
phenytoin	fenitoin, fenitoine, fenytoin, fenytoine, phenytion, phenitoin, phenitoine, phenytoine	27
propranolol	popranolol, popranolole, propanalol, propanalole, propanolol, propranolole	252
sertraline	sertalin, sertaline, sertralin, setralin, setraline	14
trazodone	tradozon, tradozone, trazadon, trazadone, trazodon	32
venlafaxine	vanlafaxin, vanlafaxine, venlafaxin, venalfaxin, venalfaxine	12
acetylcysteine	acetlycystein, acetlycysteine, acetycystein, acetycysteine, acetylcisteine, acetylcistein, acetylcistin, acetylcistine, acetylcystein, acetylcystin, acetylcystine	121
capsaicin	capsacin, capsacine, capsaicine, capsaisin, capsaisine, capsicain, capsicaine, capsicin, capsicine, caspaicin, caspacin, caspacine, caspaicine, caspaisin, caspaisine, caspicain, caspicaine, caspicin, caspicine	21
chloroquine	chloraquin, chloraquine, chloroquin, cloroquin, cloroquine, chlorokin, chlorokine, chlorquin, chlorquine, kloroquin, kloroquine	55
domperidone	dompederon, dompederone, domperadon, domperadone, domperedon, domperedone, domperidin, domperidine, domperidon, domperodon, domperodone, donperidon, donperidone, doperedon, doperedone	12
doxepin	doksapin, doksapine, doksepin, doksepine, doxapin, doxapine, doxepen, doxepene, doxepine, doxpin, doxpine	54
fludarabine	fludarabin, fludarebin, fludarebine, fludaribin, fludaribine, fluodarabin, fluodarabine, fudarabin, fudabarine, fudarebin, fudarebine, fudaribin, fudaribine, fuodarabin, fuodarabine, fudabarine	36
fluocinolone	flosinolon, flosinolone, floucinolon, floucinolone, floucynilon, floucynilone, flousinolon, flousinolone, flucinolon, flucinolone, fluocinalon, fluocinalone, fluocinilon, fluocinilone, fluocinolon, fluosinolon, fluosinolone, fluosynolon, fluosynolone, flusinolon, flusinolone	4
hydrocortisone	hidrocortason, hidrocortasone, hidrocorteson, hidrocortesone, hidrocortison, hidrocortisone, hidrocortyson, hidrocortysone, hydrecortison, hydrecortisone, hydrocortason, hydrocortasone, hydrocorteson, hydrocortesone, hydrocortison, hydrocortyson, hydrocortysone	12
lopinavir	lopinavire, lopinevir, lopinevire, lopinivir, lopinivire, lopinovir, lopinovire, lopynavir, lopynavire, lovinipir, lovinipire, olpinavir, olpinavire, olpynavir, olpynavire	2
mannitol	manatol, manatole, manetol, manetole, manitol, manitole, mannatol, mannatole, mannetol, mannetole, mannotol, mannotole, manotol, manotole	58
melatonin	malatonin, malatonine, melatonine, melatonnin, melatonnine, meletonin, meletonine, melitonin, melitonine, mellatonin, mellatonine	17
midazolam	medazalam, medazalame, medazolam, medazolame, midazalam, midazalame, midazolame, midazolan, nidazolam, nidazolame	11
minoxidil	manoxidil, manoxidile, menoxidil, menoxidile, minoksidil, minoksidile, minoxadil, minoxadile, minoxedil, minoxedile, minoxidil, minoxidile, minoxidile, minoxidill, minoxidille, minoxidyl, minoxidyle, minoxodil, minoxodile, minoxydyl, minoxydyle, mynoxidil, mynoxidile, mynoxidyl, mynoxidyle, mynoxydil, mynoxydile, mynoxydyl, mynoxydyle	1
naloxone	maloxon, maloxone, nalloxon, nalloxone, nalokson, naloksone, naloxen, naloxene, naloxin, naloxine, naloxon, neloxon, neloxone, niloxon, niloxone, noloxon, noloxone	32
olanzapine	olanapin, olanapine, olanzapin, olanzepin, olanzepine, olanzipine, olenzapin, olenzapine, ollanzapin, ollanzapine, olapazin, olapazine	29
oxycodone	oksicodon, oksicodone, oxecodon, oxecodone, oxicodon, oxicodone, oxycodon, oxydocon, oxydocone	3
oxytetracycline	oxitetraciclin, oxitetracicline, oxitetracyclin, oxitetracycline, oxytetracyclin, oxytetracycline, oxytetraciclin, oxytetracicline, oxitetracilin, oxitetracicine, oxitetracylin, oxitetracyline, oxytetracylin, oxytetracyline, oxytetracilin, oxytetraciline, oxitetracicin, oxitetracicine, oxitetracycin, oxitetracycine, oxytetracycin, oxytetracycine, oxytetracicin, oxytetracicine	43
paracetamol	paracetamole, paracettamol, paracettamole, paracetemol, paracetemole, paracetimol, paracetimole, parecetamol, parecetemole, parecetemole, paracitamol, paracitamole, paricetimol, paricetimole, parasetamole, parasettamol, parasettamole, parasetemol, parasetemole, parasetimol, parasetimole, paresetamol, paresetemole, paresetemole, parasitamol, parasitamole, parisetimol, parisetimole, rapacetamol, rapacetamole, rapacettamol, rapacettamole, rapacetemol, rapacetemole, rapacetimol, rapacetimole, rapecetamol, rapecetemole, rapecetemole, rapacitamol, rapacitamole, rapicetimol, rapicetimole	17
penicillin	nepicillin, nepicilline, nepicyllin, nepicylline, panicillin, panicilline, panicyllin, panicylline, penacillin, penacilline, penacyllin, penacylline, penecillin, penecilline, penecyllin, penecylline, penicilin, peniciline, penicilline, penicylin, penicyline, penicylline, penisillin, penisilline, penisyllin, penisylline	64
perphenazine	perfenazin, perfenazine, perphenazin, perphenyzin, perphenyzine, prephenazin, prephenazine	7
prednisolone	pednisolon, pednisolone, prednisalon, prednisalone, predniselon, predniselone, prednisolin, prednisoline, prednisollon, prednisollone, prednisolone, prednysolon, prednysolone, prendisolon	3
pyridoxine	piridoxin, piridoxine, pirydoxin, pirydoxine, pyriddoxin, pyriddoxine, pyridoxin, pyrrhidoxin, pyrrhidoxine, pyrridoxin, pyrridoxine, pyrydoxin, pyrydoxine	37
tacrolimus	tacrolymus, tarcolimus, tarcolymus, tecrolimus, tecrolymus, ticrolimus, ticrolymus	3
testosterone	testasterone, testesterone, testisterone, testostarone, testosteron, testostirone, testasteron, testesteroe, testisteroe, testostaron, testostiron	28
treosulfan	treosulfam, treosulfam, treosulfame, treosulfan, treosulfan, treosulfane, treosulphan, treosulphane, triosulfan, triosulfane, trosulfan , trosulfane	11
729,306 hits		8323 hits (1.14%)