June 1998
`Volume 87, Number 6
`
`MINIREVIEW
`
`Current Perspectives on Pain upon Injection of Drugs
`
`GAYLE A. BRAZEAU,*,† BRIAN COOPER,‡ KARI A. SVETIC,† CHARLES L. SMITH,§ AND PRAMOD GUPTA|
`
`Contribution from Department of Pharmaceutics, College of Pharmacy, Box 100494 JHMHC, Department of Oral and Maxillary
`Surgery and Diagnostic Sciences, College of Dentistry, Box 100416, Parker E. Mahan Facial Pain Center, College of Dentistry,
`Box 100437, JHMHC, University of Florida Gainesville, Florida 32610, and TAP Holdings, 2355 Waukegan Road,
`Deerfield, Illinois 60015.
`
`Final revised manuscript received March 12, 1998.
`Received August 12, 1997.
`Accepted for publication March 16, 1998.
`
`Abstract 0 A limitation in the administration of parenteral products
`is the pain caused upon injection.
`Injection site pain has been
`predominately associated with intravenous, intramuscular, and sub-
`cutaneous administration.
`It becomes important for the formulation
`scientist to have a basic understanding of the physiology underlying
`the pain process, as well as the pharmaceutical factors associated
`with injection site pain.
`Initially, this review will provide the reader
`with a primer on the mediation of pain in the periphery and a
`compilation of those drugs that have been associated with pain on
`injection.
`In addition, this review will present important considerations
`and general formulation approaches or methods that have been used
`to overcome pain on injection. Finally, a brief overview of the various
`experimental systems used to investigate injection site pain is
`discussed.
`
`Introduction
`Pharmaceutical formulators are increasingly being asked
`to investigate the use of parenteral routes of drug admin-
`istration. One likely explanation is the increasing interest
`in the therapeutic development and use of peptide or
`protein drugs and gene delivery, which due to their limited
`
`(352) 846-2724. Fax:
`* Corresponding author. Phone:
`4447. E-mail: brazeau@cop.health.ufl.edu.
`† Department of Pharmaceutics, University of Florida.
`‡ Department of Oral and Maxillary Surgery and Diagnostic Sci-
`ences, University of Florida.
`§ Parker E. Mahan Facial Pain Center, University of Florida.
`| TAP Holdings.
`
`(352) 392-
`
`oral bioavailability often require parenteral administration.
`Furthermore, the shift of patient care to the ambulatory
`setting has necessitated the investigation of the routes of
`drug administration that can be useful in the home health
`care environment for traditional small molecular weight
`molecules. Consequently, the formulator is often asked to
`provide successful short-term and/or long-term delivery of
`these therapeutic modalities, while maintaining stability
`and patient acceptability. The major routes of administra-
`tion that have been utilized in preclinical and clinical trials
`are the intravenous, subcutaneous, and intramuscular
`routes of administration.1 Other less commonly used
`routes include intraperitoneal, intrathecal, intracardiac,
`intracisternal, intralesional, intrapleural, intrauterine, and
`intradermal. However, these latter routes are frequently
`associated with specific drugs and therapies and limited
`to hospitalized patients.
`From a formulator’s perspective, the development of
`parenteral products requires optimization with respect to
`adequate stability, solubility, injectability, and tolerability
`of the therapeutic modality. The focus in the pharmaceuti-
`cal literature, to date, has primarily been on understanding
`the factors and issues associated with developing formula-
`tions that achieve the requisite stability and solubility. It
`has also been critical to ensure the relative ease in the
`injectability of the product by minimizing viscosity or by
`providing guidelines on the safe route and rate of drug
`administration.
`In contrast, pain or tissue damage upon injection of
`formulations (e.g., tolerability), while critical to the clinical
`(and even financial) success of these products, is less well
`understood by formulation scientists. The extent and
`
`© 1998, American Chemical Society and
`American Pharmaceutical Association
`
`S0022-3549(97)00315-8 CCC: $15.00
`Published on Web 04/21/1998
`
`Journal of Pharmaceutical Sciences / 667
`Vol. 87, No. 6, June 1998
`
`Medac Exhibit 2022
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
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`

`

`mechanism of tissue irritation and/or damage following
`parenteral administration, as well as methods to minimize
`or eliminate these issues, have been discussed somewhat
`in the pharmaceutical literature.2-8 However, the under-
`lying factors responsible for pain upon injection, which may
`occur without direct toxicity to the injected tissue, have
`not received as much attention by formulators in the
`development of new products. Possible explanations for
`the limited knowledge in understanding the extent and
`mechanisms of injection-associated pain include (1) the lack
`in the number and type of models available to study the
`physiology and mechanisms of pain, (2) the difficulty,
`variability, and cost associated with using animal models
`to evaluate pain, and (3) the necessity to use subjective
`versus objective measures (which often involve extensive
`experimental setups) to evaluate the extent of pain and/or
`methods to reduce pain either in animals or humans.
`While it is critical to characterize the extent of pain upon
`injection during the development of parenteral formula-
`tions, these studies are often not conducted due to the
`limitations described above. In contrast, the screening of
`formulations for their potential to cause tissue damage (e.g.,
`hemolysis, muscle damage) can be done relatively easily
`using experimental systems which are readily available,
`require a short time frame, and include the appropriate
`positive and negative controls.2-11 The question to be
`raised at this point is whether there is a relationship
`between pain and tissue damage. Three types of relation-
`ships between pain and tissue damage are possible and
`need to be considered. First, it is possible that a given
`formulation can cause tissue damage that results in pain
`at the injection site. If this were the case, screening of
`formulations for their potential to cause tissue damage
`provides a reasonable first approach to rule out unaccept-
`able formulations. Use of tissue toxicity screening methods
`can provide the formulator with a rational approach to
`develop and select the optimal formulations with respect
`to the desired physicochemical properties and tissue toler-
`ability.
`Second, in contrast, there may be drugs or formulations
`associated with pain upon injection where there is no
`indication of any type of tissue damage at the site of
`injection. This relationship is more problematic because
`it is possible that formulations that did not cause tissue
`damage in preclinical studies are now reported to cause
`pain on injection during the subsequent clinical trials. If
`volunteers and patients report moderate or severe pain
`with injection during clinical studies, this could potentially
`stop or limit further development of the product. It would
`be useful
`in this case to have methods to screen a
`parenteral formulation early during development for the
`potential to cause pain.
`Finally, it is possible for a given formulation to cause
`tissue damage that is not associated with pain upon
`injection. The difficulty in this particular scenario may
`occur if the formulation requires repeated injections that
`could cause irreversible changes in the tissue at the site.
`It subsequently becomes the responsibility of those indi-
`viduals involved in the preclinical and clinical trials for
`drugs designed for repeated administration to include in
`their experimental methods the assessment of the long-
`term impact of repeated administration on tissue at the
`injection site.
`Since at this stage the formulator cannot be sure of the
`relationship between tissue damage and injection site pain,
`it is recommended that studies investigating the extent of
`pain and or tissue damage be included during the design
`of parenteral formulations. Furthermore, it becomes criti-
`cal for the formulator to be aware of the physiology
`associated with pain and the factors that have been
`
`668 / Journal of Pharmaceutical Sciences
`Vol. 87, No. 6, June 1998
`
`reported to cause pain upon injection. The specific focus
`of this review will be to provide the formulator with (1) a
`basic primer to understanding the peripheral mediation of
`pain, (2) a discussion of those factors which have been
`reported to cause pain on injection, (3) a discussion of
`experimental systems to study pain on injection, (4) a
`report of those drugs reported to cause pain upon injection,
`and (5) a discussion on approaches which have been used
`to offset pain associated with injection. At this stage, there
`is no clear method that has been associated with a
`reduction of injection site pain.
`For information on the specific methods to characterize
`the extent and mechanisms of tissue damage with parenter-
`al administration, readers are referred to studies by
`Brazeau,2,3 Gupta,4 Comerski,5 Sutton,6-8 and Yalkowsky.9-11
`
`The Mediation of Pain by the Peripheral Nervous
`System
`The anatomy and physiology of the pain system will be
`limited to a discussion of the peripheral nervous system,
`as it is this component that has principal bearing on the
`pain upon injection. Where appropriate, suggestions of
`possible mechanisms by which a parenteral formulation
`could interact with the pain system will be briefly dis-
`cussed.
`The sensation of pain is mediated in the periphery by
`multiple sets of specialized afferents (sensory fibers) called
`nociceptors. Like other sensory neurons, nociceptor cell
`bodies are found clustered in paired ganglia located within
`each spinal vertebra (see Figure 1). Each ganglion cell has
`a peripheral process (axon) that extends out to tissue (e.g.,
`muscle) and a central process that travels into the spinal
`cord to communicate with the central nervous system.
`Nociceptors have been subclassified on both anatomic and
`functional bases. The diameter of the peripheral process
`(1-15 (cid:237)m) and the presence or absence of a nonneuronal
`covering (myelin) determine the rate at which afferents
`conduct impulses (action potentials). This forms the basis
`for anatomic criteria by which afferents are classified. It
`was formerly believed that pain sensation derived solely
`from the small diameter, slowly conducting, thinly myeli-
`nated and unmyelinated subgroups (called A(cid:228) and C,
`respectively); however, recent evidence indicates that no-
`ciceptors are represented in all three major afferent
`categories. This includes the large diameter, fast conduct-
`ing groups (A(cid:226)), traditionally associated with touch sensa-
`tion. It is worth noting that a parallel nomenclature is
`used for cutaneous (A(cid:226), A(cid:228), and C) and deep (muscle,
`viscera) afferents (group II, group III, and group IV). This
`distinction is mainly historical, as these classes are gener-
`ally identical in function.12-16
`While there is no absolute nomenclature for nociceptors,
`the most accepted naming system divides pain afferents
`according to their functional capacities. Therefore, noci-
`ceptors that respond to intense mechanical and thermal
`stimuli are mechanothermal nociceptors (MH).
`If they
`come from A(cid:228) or C fiber groups, they are called AMH and
`CMH, respectively.13 If they also have a chemical response,
`they are called polymodal nociceptors. Polymodal nocicep-
`tors are found in both myelinated and unmyelinated
`categories.17,18
`Nociceptors are usually silent at rest. That is, in the
`absence of intense stimuli there is no activity. However,
`some nociceptors of the C (or group IV) class maintain a
`slow continuous activity rate (usually <1 Hz).
`It is
`important to note that even when stimulated, nociceptor
`activity is possible in all classes without any sensation.
`That is because activity in a nociceptive ending will not
`
`Page 00002
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`

`

`Figure 1sInnervation of tissue by peripheral afferents of the DRG. Pairs of dorsal root ganglia lie along the side of the spinal cord (left panel) and innervate
`peripheral tissues. Complimentary innervation of the head and oral tissues are supplied by paired trigeminal root ganglia. In the exploded section, innervation of
`muscle and skin are shown as relevant examples. Many thousands of cell bodies in each DRG contribute axons into peripheral nerves which have endings in
`all forms of peripheral tissue. Cell bodies for both nociceptive and non-nicoceptive sensoary afferents are found in the ganglia. Transduction (encoding) of sensory
`events occurs in the receptor ending (see Figure 2). The cell body synthesizes functional components of the neuron and ships them to both peripheral endings
`and to central synapses within the spinal cord.
`
`necessarily be transmitted past the first relay in the spinal
`cord. Therefore, some critical level of activity is required
`before a sensation is reported. Once this critical frequency
`is achieved, the particular sensation is dependent upon the
`type of nociceptor activated. Different forms of sensation
`are associated with different subgroups. Activity in A(cid:226) or
`A(cid:228) nociceptors is associated with brief, intense burning
`(e.g., a match burn) or sharp, crushing or tearing sensa-
`tions. Activity in C fiber nociceptors is associated with
`diffuse burning (e.g., sunburn) or aching sensations.19,20
`Nociceptors are distinguished from other afferent groups
`(those mediating touch, tickle, pressure, warmth, cold) by
`their transducing (or encoding) capacity. All sensory
`afferents have characteristic response ranges that permit
`them to encode their preferred stimuli with precision.
`Accordingly, the range of neural discharge (action potential
`frequency in hertz) of nociceptors is tuned to reflect forces
`(or heat) that potentially damage tissue.12,21,22 Therefore,
`nociceptors of the cornea are very sensitive and have a
`narrow response range while nociceptors of the skin have
`a very high threshold and broad response range.21,23,24
`Typically, nociceptor activity begins well before tissue
`damage is imminent but reaches a peak as tissue failure
`forces (tissue destruction) are approached.22 This feature
`is important in understanding how injection volume can
`affect pain upon injection. The sensitivity of nociceptors
`to tissue distention is related to the fragility of the tissue
`injected. However, whether fragile tissues are stretched
`will be dependent upon the ability of the whole tissue to
`accept (disperse) large volumes of fluid without introducing
`tissue distortion into fragile tissue components. In this
`regard, it is important to remember that human tissue is
`generally a composite of both weak and tough components.
`This is one reason injection speed, injection volume, or site
`appears in some way to affect pain upon injection.
`Nociceptor activation is ultimately dependent upon the
`ion channels present in the nociceptor endings (Figure 2).
`Mechanical nociception is dependent on the stretch-
`activated channels.25,26 When mechanical forces in tissue
`grow (tissue is stretched or compressed), stretch-activated
`channels open and neural discharge is initiated. In addi-
`tion to direct actions of fluid volume (see above), intense
`mechanical forces may be mimicked in nociceptor mem-
`
`Figure 2sSimplified representation of the peripheral ending of a nociceptor.
`The drawing illustrates mechanisms by which nociceptor endings may interact
`with parenterals. These include interaction of the injected solution with the
`ending via pH or osmotic pressure, release of mediators from intact cells
`(e.g., PGE2), damaged cells (e.g., ATP), or from local vascular bed sources
`(5HT and BK). Weak passive currents evoked by these events may initiate
`action potentials at voltage activated Na+ and K+ channels. A minimum action
`potential frequency is required for perception. In the interest of simplicity, the
`nociceptor shown represents a composite of subtypes that include A(cid:228), C
`mechanothermal and chemically sensitive (polymodal) afferents. Specific
`receptors expressed for each ligand are shown by near association of the
`ligand. Some receptors form channels while other receptors are linked to
`channels by G proteins. Key: ATP, adenosine triphosphate; BK, bradykinin;
`Ca2+, calcium; CGRP, calcium gene related peptide; G, G protein; H+, proton;
`Na+, sodium; K+, potassium; PGE2, prostaglandin E2; SAC, stretch-activated
`channel; SP, substance P.
`branes when hyposmotic fluids force water into cells.
`Expansion of neural membranes, due to water entry, will
`have profound influences on nociceptor activity, because
`membrane stretch mimics intense mechanical forces in
`tissue. Similarly, hyperosmotic influences that draw water
`from neural endings could activate compression sensitive
`channels with similar consequences. However, compres-
`sion sensitive channels are still hypothetical.
`
`Journal of Pharmaceutical Sciences / 669
`Vol. 87, No. 6, June 1998
`
`Page 00003
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`

`

`Thermal nociceptors are a major subgroup of the noci-
`ceptive population. The mechanism of thermal nociception
`is not known but may be due to the release of intracellular
`stores of Ca2+.27 Agents that release Ca2+ from intracel-
`lular stores (calcium ionophores) may mimic the thermal
`transduction response of nociceptors. The capacity of
`parenterals to release intracellular Ca2+ has not received
`attention but could explain the injection site pain associ-
`ated with some agents.
`As noted above, nociceptors that have chemical as well
`as mechanical and thermal response capacities are called
`polymodal. Mechanical and thermal responses are prima-
`rily designed to protect tissue from external, superficial
`stimuli. In contrast, chemical responses of nociceptors are
`designed to detect the aftermath of tissue damage. Vas-
`cular cells, inflammatory cells, and blood-borne precursors
`are sources of proinflammatory agents (e.g., bradykinin,
`serotonin, prostaglandins) that are recognized by nocicep-
`tors.28 In addition, damaged cells release ATP, a potent
`activator of nociceptors. Specific receptors, present in
`nociceptor endings, recognize and bind these agents (e.g.
`bradykinin receptors, serotonin receptors, prostaglandin
`receptors, and ATP receptors).29 Nociceptors are diverse
`in their expression of these chemical receptors. The
`binding of chemical agents results in ion flow that excites
`nociceptors, causes immediate pain, and can induce local
`and distal events that contribute to long term “soreness”
`or hyperesthesia.
`In addition, other receptors detect
`general tissue events associated with injury, such as
`decreased pH.30 Tissue acidity increases when vascular
`supply is lost or diminished due to trauma. The introduc-
`tion of parenterals, whose pH mimics a damaged environ-
`ment, will open proton sensitive channels and powerfully
`activate nociceptors.
`If parenterals bring about tissue
`damage, proinflammatory agents will both directly activate
`nociceptors and contribute to hyperesthesia in the injection
`field. Central nervous system mechanisms are also likely
`to contribute to long-term soreness at injection sites.31-32
`Central nervous system (CNS) mechanisms of hyperesthe-
`sia are beyond the scope of this review. It is sufficient to
`recognize that these CNS mechanisms are dependent upon
`peripheral nociceptor activity for both initiation and main-
`tenance.
`Direct interaction of active drug, antimicrobials, or other
`additives with voltage activated ion channels is yet another
`means by which parenterals could influence the pain
`system. The nociceptive neuron is able to conduct signals
`(action potentials) because it has devised methods of
`separating ions (Na+, K+, Ca2+) and controlling their flow
`across membranes through selective, voltage-activated ion
`channels.33 In general, Na+ flow favors signal generation
`and K+ flow opposes signal generation. Nociceptors are
`activated, or their activity is modulated, by chemicals that
`interact with ion control mechanisms. The increase of ion
`flow in some channels (Na+) or the decrease in ion flow in
`other channels (K+) can cause or greatly enhance pain by
`modifying the range or rate of nociceptor discharge. Many
`naturally occurring and synthetic drugs interfere with ion
`control mechanisms at relatively low concentrations (mi-
`cromolar to picomolar). The most well recognized of these
`are the plant and animal toxins. It is unclear to what
`extent drugs and/or formulation excipients in parenteral
`products could affect these ion control mechanisms.
`Plants and animals have evolved chemical defenses or
`toxins [(e.g. capsaicin (plant toxin), melittin (bee toxin),
`dendrotoxin (snake toxin), charybdotoxin (a scorpion toxin)]
`that bind to ion channels or otherwise interact (or disrupt)
`nociceptor membranes.34,35 By holding channels open (e.g.,
`Na+ channels) or preventing channels from opening (e.g.,
`K+ channels), plant and animal toxins are able to induce
`
`670 / Journal of Pharmaceutical Sciences
`Vol. 87, No. 6, June 1998
`
`intense pain. Potentially, any foreign agent (e.g., anti-
`biotic) introduced into tissue by injection could interact
`with ion channels by binding directly to the channel or
`blocking flow of ions through the channel pore. Agents
`could also interfere with the automatic “inactivation”
`process of ion channels (e.g., Na+), thereby prolonging the
`duration of opening or preventing them from closing.
`Blocking of K+ ion flow or increasing Na+ ion flow could
`greatly enhance pain sensations either by directly activat-
`ing nociceptors or increasing activity in those nociceptors
`which maintain a slow spontaneous discharge (see above).
`
`Specific Mechanisms of Intramuscular and
`Subcutaneous Pain
`Recent studies have investigated the specific mecha-
`nisms of intramuscular and subcutaneous pain. Graven-
`Nielson and co-workers have examined the factors associ-
`ated with muscle pain in humans using hypotonic, isotonic,
`and hypertonic saline solutions by using microdialysis.36-37
`It was reported that only a hypertonic saline solution
`resulted in increased intramuscular pressure and that pain
`activation in skeletal muscle is related to increased sodium
`and potassium content.36 Furthermore, it appears that
`intramuscular pain is increased by temporal (repeated
`injections) and spatial summation (injections given at
`different sites).37 For subcutaneous injections, pain ap-
`pears to be reduced when a buffer at a nonphysiological
`pH is prepared at a lower buffer capacity, to enable a more
`rapid normalization to the pH at the injection site.38
`Jorgensen and co-workers have reported that pain follow-
`ing subcutaneous administration is related to the injection
`volume.39
`
`Compounds Reported to Cause Pain on Injection
`A wide variety of drug classes have been reported to
`cause pain following parenteral administration. This list
`includes antibiotics, benzodiazepines, vitamins, iron, non-
`steroidal antiinflammatory agents, phenothiazines, local
`and general anesthetics, anticonvulsants, and peptide
`drugs. The drugs or formulations reported to cause pain,
`and potential strategies to reduce this event, are listed in
`Table 1.40-128 A review of this list indicates that pharma-
`cological agents associated with pain on injection include
`a broad array of those used in clinical practice. Further-
`more, the diversity in the structures does not seem to
`indicate specific chemical moieties or properties that can
`be linked to injection-associated pain. The reports of pain
`on injection seem to be the greatest with the penicillin,
`cephalosporin, and aminoglycoside antibiotics. In addition,
`the general anesthetics also seem to be associated with pain
`upon iv injection.
`It is unclear whether this would be
`primarily a function of their specific chemical structure,
`properties, and/or their formulations or secondary to the
`widespread use of these agents in hospitalized and ambu-
`latory patients.
`The formulator must be keenly aware of the difficulty
`in interpreting some of these experimental findings. It is
`critical for the formulator to discriminate the painful effect
`of the drug from that of the other excipients in the
`formulation. There is usually no problem when the drug
`is hydrophilic and can be readily formulated to achieve the
`desired pharmaceutical properties using an isotonic vehicle
`that is not associated with pain (e.g., normal saline). In
`contrast, for more lipophilic compounds that may require
`solubilization, complexation, or emulsification, it may be
`extremely difficult to determine the magnitude of pain
`associated with the injection of the drug molecule itself. It
`
`Page 00004
`
`

`

`Table 1sDrugs Reported To Cause Pain upon Injectiona
`
`drug class and specific agents
`
`nature of pain response
`
`method of reducing adverse response
`
`ref no.
`
`amoxicillin
`penicillin G
`
`penicillin G benzathine
`penicillin G procaine
`sodium sulbactam and ampicillin
`
`Penicillin Antibiotics
`1/3 patients pain upon injection
`irritating after im injection, sciatic nerve damage,
`irritation and dysfunction possible
`pain after sc and im injection
`pain after im injection
`pain at im site
`
`cefamandole
`cefoperazone
`cefotetan disodium
`cefoxitin
`ceftazidime sodium
`ceftriaxone
`ceftriaxone
`ceftriaxone
`cefuroxime sodium
`
`amikacin sulfate
`gentamicin sulfate
`kanamycin sulfate
`neomycin sulfate
`streptomycin sulfate
`timoxicillin
`tobramycin sulfate
`
`arthemether
`
`spectinomycin
`trospectomycin
`
`tetracycline
`
`pentamidine
`oxamniquine
`
`clarithromycin
`
`bleomycin
`methotrexate
`
`diazepam
`diazepam
`diazepam
`diazepam
`diazepam
`lorazepam
`midazolam
`
`chlorpromazine
`promethazine HCl
`
`bupivicaine
`lidocaine
`lidocaine
`lidocaine
`
`etomidate
`etomidate
`etomidate
`methoxital
`methohexitone
`propofol
`propofol
`propofol
`propofol
`
`Cephalosporin Antibiotics
`
`pain at im site
`transient pain at im site
`pain at injection site
`pain at im site
`pain at im site
`pain upon injection
`pain at im site
`pain at im site
`pain at im site
`
`Aminoglycoside Antibiotics
`local irritation and pain after im and iv administration
`local irritation and pain after im and iv administration
`local irritation and pain after im and iv administration
`local irritation and pain after im and iv administration
`local irritation and pain after im and iv administration
`pain on im injection
`local irritation and pain after im and iv administration
`Antimalarials
`
`pain at im site
`
`Aminocyclitrol Antibiotic
`
`pain at im injection site
`pain and tenderness at im injection site
`Tetracycline Antibiotics
`
`pain at im site
`
`Antiprotozoals and Antihelmintic
`pain on im injection site
`moderate to severe pain at im site for days to weeks
`Macrolide Antibiotics
`
`pain on iv injection
`
`pain on intralesional injection
`pain at im site
`
`Antineoplastics
`
`Benzodiazepines
`
`pain on injection
`pain on injection
`pain and thrombophlebitis on injection
`pain and thrombophlebitis on injection
`pain on injection
`pain at im site
`pain during im injection
`
`include lidocaine or procaine HCl
`include procaine
`
`none suggested
`none suggested
`none suggested
`
`inject deeply into large muscle mass
`include lidocaine
`include lidocaine
`none suggested
`none suggested
`include lidocaine
`none suggested
`use lidocaine or buffered lidocaine
`less painful when injected as a suspension
`rather than a solution, less pain when
`injected into the gluteus maximus or
`the vastus lateralis
`
`none suggested
`none suggested
`none suggested
`none suggested
`none suggested
`none suggested
`none suggested
`
`none suggested
`
`none suggested
`none suggested
`
`inject deeply into large muscle
`
`iv infusion
`none suggested
`
`formulate as an emulsion
`
`include lidocaine
`subcutaneous injection
`
`formulate as an emulsion
`formulate as an emulsion
`formulate as an emulsion
`formulate as an emulsion
`formulate as mixed micelles
`use sublingual administration
`none suggested
`
`Phenothiazines
`irritation after sc injection, pain after im injection
`irritation following sc injection
`
`include procaine
`none suggested
`
`Local Anesthetics
`
`General Anesthetics
`
`pain on sc injection
`pain on iv injection
`pain on sc injection
`pain on sc injection
`
`pain on iv injection
`pain on iv injection
`pain on injection
`pain on injection
`pain on iv injection
`pain on injection
`pain on iv injection
`pain on iv injection
`pain on iv injection
`
`adjust pH to 7.0
`increase pH
`addition of sodium bicarbonate
`warm solution
`
`none suggested
`none suggested
`none suggested
`formulate as an emulsion
`include lidocaine
`include alfentanil
`include lidocaine
`include lidocaine or procaine
`use antecubital fossa as injection site
`
`Journal of Pharmaceutical Sciences / 671
`Vol. 87, No. 6, June 1998
`
`40
`41
`
`41
`41
`42
`
`43
`43
`43
`44
`43
`45
`46
`47
`43
`
`48
`48
`48
`48
`48
`49
`48
`
`50
`
`51
`52
`
`53
`
`54
`55
`
`56
`
`57
`58
`
`59
`60
`61
`62
`63
`64
`65
`
`66
`67
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`68
`69
`70
`71
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`72
`73
`74
`75
`76
`77
`78
`79
`80
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`Page 00005
`
`

`

`Table 1s(Continued)
`
`drug class and specific agents
`
`nature of pain response
`
`method of reducing adverse response
`
`ref no.
`
`propofol
`propofol
`propofol
`propofol
`propofol
`propofol
`propofol
`propofol
`propofol
`
`propofol
`propofol
`propofol
`propofol
`propofol
`
`propofol
`propofol
`
`botulinum toxin A
`gallamine
`methocarbamol
`
`myochrysine (gold sodium thiomalate)
`
`epinephrine
`
`phentolamine, prostaglandin E1, and papaverine
`
`bradykinin
`erythropoietin
`erythropoietin
`erythropoietin
`erythropoietin
`erythropoietin
`follicle stimulating hormone
`heparins
`insulin
`
`diclofenac
`diclofenac
`ketorolac/trimethamine
`
`diatrizoate meglumine
`edetate calcium disodium
`haemophilus influenza type B vaccine
`immune serum globulin
`iron dextran injection
`MNrgp120 HIV-1 vaccine
`normal saline
`phenytoin
`polymixin B sulfate
`progesterone
`testosterone
`theotepa
`trimethobenzamide
`Vitamins A, D, and K
`
`a im, intramuscular; sc, subcutaneous.
`
`General Anesthetics
`
`pain on injection
`pain on injection
`pain on injection
`pain on injection
`pain on injection
`pain on iv injection
`pain on iv injection
`pain on iv injection
`pain on injection
`
`pain on iv injection
`pain on iv injection
`pain on iv injection
`pain on iv injection
`pain on iv injection
`
`pain on iv injection
`pain on iv injection
`Skeletal Muscle Relaxants
`pain at im injection site
`pain on perineurmoral injection
`pain after iv injection, irritation at im site
`Antirheumatic
`
`pain at im site
`
`use forearm veins versus dorsal hand veins
`include lidocaine
`include alizaprode instead of lidocaine
`change temperature to 4 (cid:176)C
`formulate as an emulsion
`reduce drug concentration
`use lidocaine
`use lidocaine
`use lidocaine or aspiration of blood into
`syringe before injection
`warm solution to 37 (cid:176)C
`lidocaine better in men; pethidine better in women
`place smaller concentration in the aqueous phase
`use lidocaine or aftentanil
`lidocaine reduces incidence and severity;
`thiopentone only reduces severity
`use alfentanil
`use nitroglycerin ointment at the site
`
`none suggested
`none suggested
`none suggested
`
`include lidocaine
`
`include lidocaine
`
`increase pH with sodium bicarbonate from 4.17 to 7.05
`
`Adrenergic Agents
`intense pain on injection in patients
`with chronic nerve end neuromas
`pain on injection
`Peptides and Protein Drugs
`none suggested
`pain on intradermal injection
`none suggested
`pain on sc injection
`none suggested
`pain on sc injection
`remove citrate buffer
`pain after sc injection
`use lidocaine
`pain on sc injection
`use lidocaine-prolocaine cream at the site
`pain on sc injection
`none suggested
`pain on im and sc injection
`none suggested
`pain during sc injection
`optimize needle size and shape
`pain on injection
`Nonsteroidal Antiinflammatory Agents
`irritation on im injection
`none suggested
`pain at im injection
`none suggested
`pain at im injection site
`decrease drug dose
`Miscellaneous Agents
`pain, burning, stinging after iv injection
`pain at im injection site
`pain at im injection site
`pain at im injection site
`pain after iv injection
`irritation after iv injection
`pain at im site
`pain at im site
`severe pain at im injection site
`pain after im injection
`pain on im injection
`pain at im injection site
`pain, stinging, burning after im injection
`severe local pain at im injection site
`
`none suggested
`include procaine
`subcutaneous injection
`iv infusion
`none suggested
`use water-soluble prodrug
`use lidocaine-prolocaine cream at the site
`prodrug formation
`use intravenous injection
`none suggested
`use castor oil vehicle
`none suggested
`none suggested
`none suggested
`
`81
`82
`83
`8 4
`85
`86
`87
`88
`89
`
`9 0
`91
`92
`93
`94
`
`95
`96
`
`97
`98
`99
`
`100
`
`101
`
`102
`
`103
`104
`105
`106
`107
`108
`109
`110
`111
`
`112
`113
`114
`
`115
`116
`117
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`128
`
`then becomes critical for the pharmaceutical scientist to
`characterize the extent to which a vehicle or other formula-
`tion excipients can cause pain on injection.
`A review of the literature suggests that the intramus-
`cular site is more often associated with pain upon injection
`compared to intravenous or subcutaneous administration.
`This most likely results from the prevalence of nerves in
`muscle tissue c