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WO2012075281A1 - Systèmes et procédés pour le traitement de la douleur par stimulation des fibres neurales - Google Patents

Systèmes et procédés pour le traitement de la douleur par stimulation des fibres neurales Download PDF

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Publication number
WO2012075281A1
WO2012075281A1 PCT/US2011/062882 US2011062882W WO2012075281A1 WO 2012075281 A1 WO2012075281 A1 WO 2012075281A1 US 2011062882 W US2011062882 W US 2011062882W WO 2012075281 A1 WO2012075281 A1 WO 2012075281A1
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Prior art keywords
pain
afferent
fibers
nerve fibers
stimulation
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PCT/US2011/062882
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English (en)
Inventor
Maria E. Bennett
Joseph W. Boggs
Warren M. Grill
John Chae
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SPR Therapeutics Inc
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SPR Therapeutics Inc
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Priority to CA2819599A priority Critical patent/CA2819599C/fr
Priority to AU2011336506A priority patent/AU2011336506B2/en
Publication of WO2012075281A1 publication Critical patent/WO2012075281A1/fr
Anticipated expiration legal-status Critical
Priority to AU2016200012A priority patent/AU2016200012B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36071—Pain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551—Spinal or peripheral nerve electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36017—External stimulators, e.g. with patch electrodes with leads or electrodes penetrating the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36021—External stimulators, e.g. with patch electrodes for treatment of pain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36067—Movement disorders, e.g. tremor or Parkinson disease

Definitions

  • Embodiments according to the present invention relate generally to the relief of bodily pain in an animal, such as a human, and more specifically to the treatment of pain by action potential activation in neural fibers.
  • the peripheral nervous system of an animal is comprised generally of efferent (motor) and afferent (sensory) neural fibers.
  • Efferent fibers generally carry motor action potentials from the central nervous system, while afferent fibers carry sensory action potentials to the central nervous system.
  • afferent fibers carry sensory action potentials to the central nervous system. Since the 1950' s and 1960's and the codification of the gate theory, it has been generally accepted that bodily pain results from activity in nociceptive and non- nociceptive, or somatosensory, afferent nerve fibers, and the interaction of neural signals and pathways, which are influenced by several psychological and physiologic parameters. For instance, in a healthy person, action potentials transmitted along non-nociceptive fibers do not normally generate or cause a perception of pain.
  • non-noxious stimuli and hence the activity of non-nociceptive fibers, can cause pain.
  • sensations that would not be perceived as pain in a healthy person (e.g. light pressure or touch) may actually be perceived as painful. That is, in an individual that experiences chronic pain, the non-noxious stimuli that are sensed (transduced) by non-nociceptive receptors can lead to a perception of pain.
  • nociceptive afferent activity "opens” a gate to the transmission of sensory action potentials related to noxious input
  • non-nociceptive afferent activity "closes” the gate, thereby preventing or inhibiting the transmission of such sensory signals to the brain, interrupting or reducing the perception of pain .
  • Prior methods of stimulation of nerves for the reduction of pain have focused on the stimulation of afferent neural fibers, and such focus is perhaps understandable due to the conventional wisdom in the art for the past five decades related to gate control theory.
  • prior nerve stimulation modalities used to treat pain especially with regards to peripheral nerves, recognized a narrow treatment window between stimulation settings that may achieve desired analgesia through sensory stimulation of non-nociceptive afferents and stimulation settings that reach the threshold for discomfort or motor stimulation of efferent fibers, the latter thought to be undesirable for a number of reasons.
  • recruitment of efferent fibers is thought to be actually beneficial in reducing pain.
  • the electrical stimulation of nerves, often afferent nerves, to indirectly affect the stability or performance of a physiological system can provide functional and/or therapeutic outcomes, and has been used for activating target nerves to provide therapeutic relief of pain. While prior systems and methods can provide remarkable benefits to individuals requiring therapeutic pain relief, many issues and the need for improvements still remain.
  • Electrical stimulation systems have been used for the relief of pain. Despite the recognition and use of electrical stimulation for the treatment of pain, widespread use of available systems is limited. Such limited use is thought to stem from a variety of factors, such as invasiveness of required surgical procedures (e.g. lead placement in epidural space of spinal cord or surgical dissection) , risk of surgical complications associated with such procedures (e.g. infection, hemorrhage, neurologic injury, and/or spinal fluid leaks) , the technical skill and training required to place the electrode (s) , the duration of time required to place the electrode (s) correctly, the supporting equipment (e.g. imaging equipment such as fluoroscopy) required for electrode placement, risk of device complications (e.g. migration of stimulating lead or catastrophic failure, or breakage, of such lead), and/or loss of pain relief over time.
  • invasiveness of required surgical procedures e.g. lead placement in epidural space of spinal cord or surgical dissection
  • risk of surgical complications associated with such procedures e.g. infection, hemorrhage, neurologic
  • Electrical stimulation systems may be provided as either external or implantable devices, or a combination thereof, for providing electrical stimulation to activate nerves to provide therapeutic relief of pain.
  • These "neurostiraulators” are able to provide treatment and/or therapy to individual portions of the body.
  • the operation of these devices typically includes the use of (i) an electrode placed either on the external surface of the skin, and/or (ii) a surgically implanted electrode.
  • one or more surface electrodes, cuff-style electrodes, paddle-style electrodes, spinal column electrodes, percutaneous leads, and/or leadless microstimulators incorporating integral electrodes, each having one or more electrodes may be used to deliver electrical stimulation to one or more select portions of a patient's body.
  • TENS transcutaneous electrical nerve stimulation
  • FDA U.S. Food and Drug Administration
  • TENS systems are external neurostimulation devices that employ electrodes placed on an external skin surface to activate target afferent nerve fibers below the skin surface.
  • TENS has a low rate of serious complications, but disadvantageously, it also has a relatively low (i.e., approximately 25% or less) long-term rate of success, and some of its success is attributed to a placebo effect.
  • TENS has low long-term patient compliance because it may cause additional discomfort by generating cutaneous pain signals due to the electrical stimulation being applied through the skin, the electrodes may be difficult to apply, and the overall system is bulky, cumbersome, and not suited for long-term use.
  • SCS spinal cord stimulation
  • Lead migration is the most common complication for SCS systems, occurring in up to 40% or more of the cases.
  • the active contact moves farther from the target fibers and loses the ability to generate paresthesias in the target area.
  • SCS systems attempt to address this problem by using leads with multiple contacts so that as the lead moves, the next contact in line can be selected to be the active contact. Additionally, multiple contacts can be used to guide or steer the current toward the targeted nerve fibers and away from the non-targeted nerve fibers . Although this approach may be successful, it often requires time- intensive and complex programming, adding to the overall cost of the therapy and the burden on the patient and caregiver (s) .
  • Peripheral nerve stimulation has been attempted and may be effective in reducing pain, but it previously required specialized surgeons to place cuff- or paddle-style leads on or around the nerves in a time- consuming and invasive surgical procedure.
  • Such prior procedures may include the use of ultrasound-guided lead placement in an attempt to avoid placement in muscle tissue in an attempt to coapt intimately an electrode surface with a target nerve, or approximately 3 millimeters or less from the nerve.
  • Embodiments of the present invention include improved systems and methods of pain reduction by inducing action potentials in target neural structures.
  • Action potentials may be generated or activated in efferent fibers as an alternative to or in addition to activation of afferent fibers. If an action potential is directly induced in select afferent fibers, such action potentials may be patterned so as to be biomimetic or stochastic, as explained below. Stimulation may be applied to targeted neural fibers located (1) neurologically upstream from a perceived point of pain (i.e.
  • neurologically between the perceived point of pain and the central nervous system such as to target neural fibers of nerves of passage, (2) at or near a neurological motor point, and/or (3) neurologically downstream from such motor point, where such downstream stimulation may be applied to or near a target region from which a patient is perceiving pain.
  • An embodiment of a method according to the present invention includes the step of stimulating afferent nerve fibers in a predetermined manner to generate a stochastic response of action potentials in the nerve fibers in an animal, such as a human, to reduce a perception of pain by the animal.
  • the stimulating step includes electrically stimulating the afferent nerve fibers.
  • the afferent nerve fibers may be located outside a neural receptor and outside a central nervous system of the human.
  • the afferent nerve fibers may be located between a neural receptor and the central nervous system of the human.
  • the afferent nerve fibers may innervate neural receptors, such as proprioceptors .
  • the afferent nerve fibers may be in neural communication with neural receptors, such as proprioceptors, and stimulated at a location that may be between the neural receptors and a central nervous system of the animal.
  • neural receptors such as proprioceptors
  • the afferent nerve fibers may be one or more of a plurality of types of axons, including Aa axons, such as la and lb axons, ⁇ axons, ⁇ axons, and/or C axons.
  • Aa axons such as la and lb axons, ⁇ axons, ⁇ axons, and/or C axons.
  • a method according to the present invention may further include, in addition to afferent nerve fiber activation, the step of activating efferent nerve fibers.
  • a method according to the present invention may further include the step of stimulating efferent nerve fibers to cause a contraction of a muscle to cause a plurality of responsive action potentials to be generated by the afferent nerve fibers.
  • One or more characteristics of the responsive action potentials may be sensed, and the predetermined manner of stimulation of the afferent nerve fibers may include the application of electrical stimulation to the afferent nerve fibers.
  • the electrical stimulation may include a stimulation parameter derived from the characteristic of the responsive action potentials.
  • Such characteristic of the responsive action potentials may be selected from the group consisting of: an average frequency of two or more of the responsive action potentials, an instantaneous frequency of two of the responsive action potentials, and a pattern of two or more of the responsive action potentials.
  • the characteristic is selected from the group consisting of : an average frequency of two or more of the responsive action potentials and an instantaneous frequency of two of the responsive action potentials, and the electrical stimulation is generated at a first frequency that is greater than the characteristic. Additionally or alternatively, the electrical stimulation may be delivered to the afferent nerve fibers at a second frequency for a predetermined pulse duration, the second frequency being less than the first frequency.
  • the applying step is performed for a predetermined treatment time, and the reduction of perception of pain occurs at least partially during the treatment time and at least a portion of the reduction of perception of pain is maintained after the end of the predetermined treatment time.
  • Figure 1 depicts various physiological structures for reference in connection with the following disclosure .
  • Figure 2A depicts an example of a muscle spindle (shown contained in the capsule) , including the intrafusal muscle fibers (innervated by type ⁇ (gamma) (Class ⁇ ) motor neurons (efferent axons) and by sensory neurons (afferent axons) ) .
  • the efferent (gamma) axons terminate (shown by Gamma Motor Endings) on and innervate the spindle's intrafusal muscle fibers.
  • the sensory endings of the primary (group la) afferent axons and a secondary (group II) afferent axons innervate the intrafusal fibers.
  • Figure 2B depicts intrafusal motor fibers (nuclear chain fibers and nuclear bag fibers) and their sensory innervation.
  • the group II afferent axons are shown innervating the nuclear chain fibers and the static nuclear bag fiber.
  • the group la afferent axons are shown wrapping around and innervating the nuclear chain fibers, the static nuclear bag fiber, and the dynamic nuclear bag fiber.
  • the figure also indicates which portions can be considered contractile and non-contractile.
  • Figure 2C depicts an example of how stretch alone or in combination with stimulation of a static gamma fiber or a dynamic gamma fiber can change the neural activity of the respective afferents axons innervating the fibers of the muscle spindle.
  • Activation of gamma motor neurons (efferent axons) can change the frequency (Imp/s) of neural activity and stretch-sensitivity of the afferent neurons.
  • the figure also depicts an example of the possible relative steady-state and dynamic responses that may be achieved in terms of the neural activity of an afferent neuron innervating a muscle spindle fiber.
  • Figure 3 depicts a Golgi tendon organ including collagen fibers that physically interact with afferent axons to generate an action potential thereon during stretch.
  • Figure 4A provides a diagrammatic view of electrode placement near a targeted sensory neural structure according to a sensing step of a second embodiment of a method according to the present invention .
  • Figure 4B provides a diagrammatic view of electrode placement near a targeted sensory neural structure according to a stimulating step to occur after or without the sensing step of Figure 4A.
  • Figure 5 provides a diagrammatic view of electrode placement near a targeted sensory neural structure according to a first embodiment of a method according to the present invention.
  • Figure 6A provides a diagrammatic view of electrode placement near a targeted neural structure according to a third embodiment of a method according to the present invention.
  • Figure 6B provides a diagrammatic view of a muscle contraction caused by electrical stimulation by the electrode of Figure 6A.
  • Figure 7A provides a diagrammatic view of afferent neural structure activation or firing in response to a muscle stretch.
  • Figure 7B provides a diagrammatic view of stretch receptor afferent neural structure activation, as perhaps by a weighted stretch, and stretch receptor afferent neural fiber deactivation during muscle contraction caused by electrical stimulation of efferent neural structures .
  • Figure 7C provides a diagrammatic view of a method of continuing afferent activation during the contraction of Figure 7B through stimulation of additional or alternative efferent neural structures to those efferent structures stimulated in Figure 7B.
  • the nervous system of an animal generally comprises efferent and afferent neural fibers, and prior pain reduction modalities have focused on action potential generation or activation in non-nociceptive afferent neural fibers to inhibit, or "close the gate” to, the transmission of nociceptive pain signals to the brain.
  • This has come to be known as the gate control theory of pain management.
  • Most afferent fibers, however, are not bundled only with other afferent fibers; rather, the majority of nerves found amenable to peripheral nerve stimulation are nerve bundles comprising both afferent and efferent fibers.
  • electrical stimulation may mediate pain relief by activating somatosensory pathways that may be associated with mechanoreceptors , thermoreceptors, proprioceptors, and/or chemoreceptors .
  • types of neural cells, axons, nerve fibers, or physiological structures that may be affected, such as by intra- or extra-muscle (e.g., in subcutaneous, connective, adipose, or other tissue) electrical stimulation include functional afferent types A and C axons and efferent type A axons.
  • the afferent axons may be classified as Aa
  • Aa (type la) fibers are generally recognized as being associated with the primary sensory receptors of the muscle spindle, such as for transducing muscle length and speed. These fibers are myelinated, usually having a diameter from about 9 to about 22 micrometers ( ⁇ ) , although other diameters have been observed and may be included, and a conduction velocity of about 50 to about 120 meters per second (m/s), which is known to be proportional to the diameter of the fiber for both this type and other types of myelinated fibers.
  • Aa (type lb) fibers are generally recognized as being associated with Golgi tendon organs, such as for transducing muscle contraction.
  • These fibers are myelinated, having a diameter from about 9 to about 22 micrometers ( ⁇ ) and a conduction velocity of about 50 to about 120 meters per second (m/s) .
  • ⁇ (type II) fibers are generally recognized as being associated with the secondary sensory receptors of the muscle spindle, such as for transducing muscle stretch. These fibers are also associated with joint capsule mechanoreceptors (as transduces joint angle) and all cutaneous mechanoreceptors.
  • the cutaneous mechanoreceptors may include Meissner's corpuscles, Merkel's discs, Pacinian corpuscles, Ruffini corpuscles, hair-tylotrich (for sensing stroking/fluttering on the skin or hair), and the field receptor (for sensing skin stretch) .
  • Meissner' s corpuscles are nerve endings that can be found in the skin, which transmit afferent information regarding touch (such as soft, or light, touch) and/or vibration, especially at vibration frequencies of less than 50 Hertz. These fibers are rapidly adaptive receptors that are often located below the epidermis within the dermal papillae.
  • the corpuscles may be found as encapsulated unmyelinated nerve endings, comprising flattened supportive cells arranged as horizontal lamellae surrounded by a connective tissue capsule. Examples of this corpuscle have been described as having a length of about 30 to about 140 ⁇ and a diameter of about 40 to about 60 ⁇ .
  • Merkel's discs are a type of mechanoreceptor found in the skin, hair follicles, and in the oral and anal mucosa.
  • the discs transmit afferent information regarding pressure and texture.
  • the nerve ending comprises a Merkel cell next to a nerve terminal.
  • a single afferent nerve fiber may innervate multiple nerve endings, such as 50-100 endings.
  • This mechanoreceptor is an unencapsulated, slowly adapting type I mechanoreceptor that will provide a non- or minimally-decaying response to pressure.
  • the Merkel disc receptor may have two phases of firing, dynamic and static. In the static phase, an irregular activity may be observed, which may be typical of slowly adapting type I mechanoreceptors but contrasts with the regular pattern of slowly adapting type II mechanoreceptors.
  • Pacinian corpuscles are nerve endings that may be found in the skin. They may also be found in the mesentery, between layers of muscle, and on interosseous membranes between bones. Pacinian corpuscles transmit afferent information regarding pain and pressure. For instance, these corpuscles may detect gross pressure changes and vibrations and may fire in response to quick changes in joint position. They are phasic tactile mechanoreceptors that can detect deep pressure because they are found below the skin surface, usually in the dermis, and comprise some free nerve endings.
  • Ruffini corpuscles are slowly adapting mechanoreceptors that may be present in the glabrous dermis (hairless skin) and subcutaneous tissue of humans. These corpuscles transmit afferent information regarding skin stretch, movement, position (such as position of the fingers) , and sense of control (such as slipping of objects along the skin surface) .
  • This type of receptor may have a spindle shape, and they may be found in the deep layers of the skin, allowing them to indicate continuous pressure states and mechanical joint deformation, such as joint angle change.
  • the ⁇ fibers are myelinated, usually having a diameter from about 6 to about 12 micrometers ( ⁇ ) , although other diameters have been observed and may be included, and a conduction velocity of about 33 to about 75 meters per second (m/s) .
  • ⁇ (type III) fibers are generally recognized as being associated with free nerve endings of touch and pressure (for sensing excess stretch or force), hair-down receptors (for sensing soft, or light, stroking), nociceptors of the neospinothalamic tract, and cold thermoreceptors. These fibers are thinly myelinated, having a diameter from about 1 to about 5 micrometers ( ⁇ ) and a conduction velocity of about 3 to about 30 meters per second (m/s) .
  • C (type IV) fibers are generally recognized as being associated with nociceptors of the paleospinothalamic tract, and warmth thermoreceptors. These fibers are unmyelinated, having a diameter from about 0.2 to about 1.5 micrometers ( ⁇ ) and a conduction velocity of about 0.5 to about 2.0 meters per second (m/s) .
  • Aa efferent fibers are generally recognized as being associated with extrafusal muscle fibers. These fibers are myelinated, having a diameter from about 13 to about 20 micrometers ( ⁇ ) and a conduction velocity of about 50 to about 120 meters per second (m/s) .
  • ⁇ efferent fibers are generally recognized as being associated with intrafusal muscle fibers. These fibers are myelinated, having a diameter from about 5 to about 8 micrometers ( ⁇ ) and a conduction velocity of about 20 to about 40 meters per second (m/s) .
  • a first method according to the present invention includes activating afferent fibers (e.g. type la, lb, and/or II, which may also be called Aa and/or ⁇ afferent fibers) , which are physically located in an area from or in which an animal is perceiving pain.
  • afferent fibers e.g. type la, lb, and/or II, which may also be called Aa and/or ⁇ afferent fibers
  • stimulation may activate one or more ⁇ fibers that carry afferent information from a mechanoreceptor (i.e. a sensory receptor) that responds to mechanical pressure or distortion.
  • the stimulation may be applied in muscle or in non-muscle tissue (e.g. subcutaneous, connective, adipose or other tissue) .
  • Non- limiting examples of mechanoreptor pathways that may be activated by stimulation include (1) one or more Pacinian corpuscles; (2) one or more Meissner's corpuscles; (3) one or more Merkel disc receptors; and/or (4) one or more Ruffini corpuscles.
  • the applied stimulation may mediate pain relief through the activation of nerve fibers associated with, and/or innervating, receptors that are rapidly adapting, intermediate adapting, and/or slowly adapting.
  • an electrode is preferably spaced a predetermined distance, or within a predetermined range of distances, from the target nerve fibers.
  • a second method according to the present invention comprises the step of activating one or more afferent nerve fibers that may be located outside an area from or in which an animal is perceiving pain, and may or may not be associated with the mentioned receptors .
  • Such stimulation may be beneficial to patients experiencing pain in regions no longer innervated or that were not previously innervated by the target fibers, such as those patients that may have had removal of, or damage to, their afferent receptors. Examples of such situation may be amputee phantom limb pain or tissue damage due to trauma, such as burns, or surgery.
  • Other indications in which such stimulation may provide beneficial perceived reduction in pain are pathological or disease states (e.g.
  • a nerve trunk e.g. femoral or sciatic nerve
  • large contractions may be undesirable due to the physical effect of same.
  • tissue damage or disease progression dictate or influence the placement of needles and/or electrodes; for instance, if a patient suffers from complex regional pain syndrome, it may be desirable to prevent insertion of a needle in the affected area, as it may make symptoms of the syndrome worse, but a needle may be inserted outside of the affected area with less risk.
  • the stimulation is preferably provided in one or both of two ways: (1) direct mimicked (or biomimetic) afferent stimulation and/or (2) modulated high frequency-induced stochastic response.
  • direct mimicked afferent stimulation stimulation is applied in a predetermined, random, or pseudo-random manner to mimic afferent neural activity that otherwise may naturally occur in response to activity normally sensed by the target afferents.
  • afferents including type la fibers associated with the muscle spindle (as shown in Figures 2A-B) and type lb fibers associated with Golgi tendon organs (as shown in Figure 3), and possibly others, normally respond, and fire multiple, temporally patterned action potentials in response to a muscle contraction.
  • afferent neural activity in response to applied efferent stimulation or cued, or prompted, voluntarily generated muscle activity, such as contraction or stretch—may be recorded and/or analyzed, as diagrammatically depicted in Figure 4A.
  • the recorded or analyzed pattern may be obtained directly from the animal to be relieved of pain, may be obtained directly from an animal that is not the animal to be relieved of pain (live model), may be calculated or modeled from one or more patterns obtained from one or more animals (including or excluding the animal to be relieved of pain), and/or may be mathematically or otherwise artificially generated (i.e., without sampling) .
  • the predetermined pattern of afferent stimulation to be applied according to the present invention may then be established to approximate or identically mimic at least a portion of the recorded or analyzed pattern, as diagrammatically shown in Figure 4B. Additionally or alternatively, a random or pseudo-random stimulation pattern may be applied to the afferent fibers to mimic natural afferent activity.
  • the stimulation patterns applied may include variations in duty cycle and/or in stimulation waveform shape and/or pulse parameters, such as frequency, pulse width, and/or amplitude, which may be varied between applied pulses, or during a pulse, which may have the effect of modifying waveform shapes.
  • Altered stimulation patterns may additionally or alternatively utilize a pre-pulse, which may be the same or opposite polarity as a treatment pulse, and may have the same or opposite polarity thereof.
  • a pre-pulse which may be the same or opposite polarity as a treatment pulse, and may have the same or opposite polarity thereof.
  • a relatively high frequency from about 1 kHz to about 20 kHz, preferably about 4 kHz, modulated at a reduced frequency, such as about 0.1 Hz to about 1 kHz, more preferably less than 50 Hz, such as 1-30 Hz, and more preferably at about 12-16 Hz, may be used.
  • Such stimulation may generate pseudo-random patterns of activity in the affected afferent nerve fibers.
  • the treatment of pain through direct afferent fiber stimulation may demonstrate dis-sensitization of the afferent neural tissues that naturally respond to such stimulation. That is, it is generally recognized that the perception of pain, especially non-acute pain such as sub-acute or chronic pain, in mammals can be caused, worsened, and/or sustained in duration by a sensitization of afferent sensory receptors and/or the central nervous system fibers that receive direct and/or indirect signals from the afferent sensory receptors, including free nerve endings, to noxious or conventional or previously non-noxious stimuli.
  • Sensitization is the process whereby previously non-noxious stimuli are perceived as painful, and this is an integral part of the development and maintenance of chronic pain (as opposed to the acute, healthy pain response) .
  • Such sensitization may result from non-nociceptive primary afferents (e.g. ⁇ ) sprouting to make inappropriate and/or additional connections in the spinal cord, from the loss of inhibition in the central nervous system (e.g. spinal cord, and/or brain), and from plasticity resulting from changes in functional connectivity.
  • afferent fiber stimulation for the treatment of pain is that such stimulation may actually permanently, or at least long-term, reverse the sensitization process that formed the basis for the chronic pain being treated.
  • the effects of the afferent stimulation for the treatment of pain chronologically outlast the treatment duration, and such effects may exponentially outlast the treatment duration.
  • a treatment cycle such as a three-week treatment cycle
  • dis-sensitization may be demonstrated and the pain reduction experienced at approximately the stimulation treatment duration after the end of the treatment cycle is maintained for more than 17 times the treatment duration.
  • a patient reported a pain level of 6 prior to treatment, and a pain level of 2 at a time that is about one month after a treatment cycle (such as a three-week treatment cycle) , there has been demonstrated a high probability that the patient will report a pain level of 2 at a time that is about one year after the completion of the treatment cycle.
  • a treatment cycle such as a three-week treatment cycle
  • Systems and methods according to the present invention may be used to treat pain felt in a given region of the body by stimulating neural fibers associated with, disposed on, or innervating muscle, subcutaneous, connective, adipose, or other tissue that may be close to or some distance away from a "nerve of passage" in a region that is superior (i.e., cranial or upstream toward the spinal column) to the region where pain is felt.
  • Neural impulses comprising pain felt in a given muscle, organ, or cutaneous region of the body pass through spinal nerves that arise from one or more nerve plexuses.
  • the spinal nerves in a nerve plexus which comprise trunks that divide by divisions and/or cords into branches, comprise "nerves of passage.” It has been discovered that applying stimulation in a muscle near a targeted nerve of passage relieves pain that manifests itself in a region that is inferior (i.e., caudal or downstream from the spinal column) from where stimulation is actually applied.
  • An example of nerves of passage stimulation may be found in U.S. Patent Application Number 12/653,023, filed on December 7, 2009, and entitled “Systems and Methods to Place One or More Leads in Tissue to Electrically Stimulate Nerves of Passage to Treat Pain," published as US2010/0152808, which is incorporated by reference herein in its entirety
  • the percutaneous or implanted lead and/or electrode may be placed in the muscle (e.g. deltoid) that is experiencing the pain near, or within a therapeutically effective distance from, the point where a motor nerve enters the muscle (i.e., the motor point) .
  • Phantom pain (a type pain that may be experienced, e.g., post-amputation) is one example of the effectiveness of "nerves of passage" stimulation, because the bodily area in which phantom pain is perceived to originate does not physically exist.
  • a lead and/or electrode cannot be physically placed in the muscles that hurt, because those muscles were amputated.
  • stimulation in a muscle, subcutaneous, connective, adipose, or other tissue that has not been amputated at a therapeutically effective distance from a targeted nerve of passage that, before amputation, preferably natively innervated the amputated muscles, phantom pain can be treated.
  • An example of the treatment of post-amputation pain may be found in U.S. Patent Application Number 12/653,029, filed December 7, 2009, and entitled "Systems and Methods To Place One or More Leads in Tissue for Providing Functional and/or
  • Chronic, sub-acute, or acute pain in existing, non-amputated muscle, subcutaneous, connective, adipose, or other tissue can also be treated by "nerves of passage” stimulation.
  • nerves of passage By applying stimulation to or near a targeted nerve of passage that innervates the region where chronic, sub-acute, or acute pain is manifested, the pain can be treated.
  • a lead and/or electrode can be placed in muscle, subcutaneous, connective, adipose, or other tissue that is conveniently located near a nerve trunk that passes by the electrode and/or lead on the way to the painful area.
  • the lead and/or electrode may be placed in a muscle, subcutaneous, connective, adipose, or other tissue that is not necessarily the target (painful) tissue, but rather in a muscle or other tissue that is upstream from the painful region, because the proximal muscle or other tissue presents a convenient and useful location to place the lead and/or electrode.
  • the lead and/or electrode may be placed in a muscle, subcutaneous, connective, adipose, or other tissue having more than one region, to stimulate a nerve to treat the perception of pain from a different region of the same muscle or tissue.
  • an electrode may be placed generally near the top of the leg (near femoral nerve (1-2 cm below femoral crease)) in a first region of the Sartorius muscle, to relieve pain felt in the inner thigh near the knee (downstream) , in a second region of the Sartorius muscle.
  • the systems and methods make possible the treatment of chronic or acute pain in which muscle contraction cannot or should not be evoked (e.g. in the case of amputation pain in which the target area has been amputated is no longer physically present) or is otherwise undesirable, or other cases of nerve damage either due to a degenerative diseases or condition such as diabetes of impaired vascular function (in which the nerves are degenerating, and may be progressing from the periphery), or due to trauma.
  • a degenerative diseases or condition such as diabetes of impaired vascular function (in which the nerves are degenerating, and may be progressing from the periphery), or due to trauma.
  • the systems and methods make possible the placement of one or more stimulation leads and/or electrodes in regions distant from the motor point or region of pain, e.g., where easier access or more reliable access or a clinician-preferred access be accomplished; or in situations where the motor nerve point is not available, damaged, traumatized, or otherwise not desirable; or in situations where it is desirable to stimulate more than one motor point with a single lead and/or electrode; or for cosmetic reasons; or to shorten the distance between the lead and its connection with a pulse generator; or to avoid tunneling over a large area or over or across a joint, where the latter may contribute to device failure.
  • a third method according to the present invention comprises the step of activating one or more motor (efferent) axons (type Aa or ⁇ ) which can, in turn, mediate pain relief by activating extrafusal muscle fibers and/or intrafusal muscle fibers.
  • Activation of extrafusal muscle fibers e.g. via activation of motor (Aa) axons
  • motor (Aa) axons) can generate and/or modulate responsive afferent activity by contracting muscle fibers, producing tension, and/or causing skeletal movement.
  • the action e.g.
  • contraction, tension, movement, etc) produced by efferent activity may be transduced by sensory endings or fibers and transmitted via afferent fibers to the central nervous system, which can mediate pain relief.
  • Activation of intrafusal muscle fibers e.g. via activation of motor ( ⁇ ) axons
  • can modulate and/or generate afferent activity by changing afferent firing rate or pattern e.g. the relative base or steady-state firing frequency, average thereof, and/or the transient firing frequency such that the running average may or may not vary over time according to a pattern or non- patterned sequence
  • afferent firing rate or pattern e.g. the relative base or steady-state firing frequency, average thereof, and/or the transient firing frequency such that the running average may or may not vary over time according to a pattern or non- patterned sequence
  • the afferent' s sensitivity to mechanical or other stimuli such as stretch, vibration, muscle contraction, etc.
  • One method of providing pain relief is to activate neurons (or neural structures) innervating (or considered part of) proprioceptors, modifying proprioception.
  • the neural receptors associated with or innervated by afferent axons
  • EMG electromyography
  • the muscle contraction may cause natural afferent neural activity in response, thereby mediating pain relief.
  • Electrical stimulation of efferent neural structures may or may not recruit afferent fiber activation. That is, a method according to the present invention may include a step of recruiting or activating one or more sensory, afferent axons while generating or causing a generation of an action potential in one or more motor, efferent axons. Alternatively, only efferent axons may be recruited by stimulation. For instance, when disease (e.g.
  • the treatment of pain through efferent fiber stimulation may demonstrate at least partial dis- sensitization (e.g., partial, or complete, temporary or permanent reduction of neurological hypersensitization) of at least a portion of the nervous system through activation of afferent neural tissues that naturally respond to such stimulation. That is, it is generally recognized that the perception of pain in mammals is caused by a sensitization of afferent sensory receptors, including free nerve endings, to noxious or conventional or previously non-noxious stimuli. Sensitization is the process whereby previously non-noxious stimuli are perceived as painful, and this is an integral part of the development and maintenance of chronic pain (as opposed to the acute, healthy pain response) .
  • afferent sensory receptors including free nerve endings
  • Such sensitization may result from non-nociceptive primary afferents (e.g. ⁇ ) afferents sprouting to make additional connections in the spinal cord, from the loss of inhibition in the spinal cord, and/or from central (brain) plasticity resulting from changes in functional connectivity.
  • efferent fiber stimulation for the treatment of pain is that such stimulation may actually permanently, or at least long- term, reverse the sensitization process that formed the basis for the chronic pain being treated.
  • Dis- sensitization resulting from efferent fiber stimulation may reverse these changes through alterations in the peripheral and/or central nervous systems, including but not limited to changes in the sensitivity of peripheral sensory receptors, changes in synaptic connectivity, changes in synaptic strength, and changes in the rate and pattern of neural activity.
  • the firing pattern and rate of peripheral nervous system (PNS) (e.g. afferent) fibers may change
  • the firing pattern and rate of central nervous system (CNS) fibers may change
  • there may be changes in both the PNS & CNS there may be changes in both the PNS & CNS.
  • there may be changes in the threshold required to active the fibers in the PNS, CNS, &/or both PNS & CNS
  • the effects of the efferent stimulation for the treatment of pain chronologically outlast the treatment duration, and such effects may exponentially outlast the treatment duration.
  • a treatment cycle such as a three- week treatment cycle
  • this lasting effect is thought to demonstrate dis-sensitization, and the pain reduction experienced at approximately the stimulation treatment duration after the end of the treatment cycle may be maintained for more than 17 times the treatment duration.
  • a patient reported a pain level of 6 prior to treatment, and a pain level of 2 at a time that is about one month after a treatment cycle (such as a three-week treatment cycle)
  • the patient may report a pain level of 2 at a time that is about one year after the completion of the treatment cycle.
  • the pain level reported by the patient is less than the pain level reported prior to treatment, then at least some dis-sensitization is thought to have occurred .
  • Various systems may be utilized to implement the stimulation methods provided herein.
  • the methods may be carried out in a staged progression, which may include a percutaneous and/or transcutaneous phase.
  • the percutaneous and/or transcutaneous stimulation phase may be followed by an implanted, percutaneous, and/or transcutaneous stimulation phase.
  • Preferred percutaneous systems may be found in U.S. Patent Application Serial No. 12/462,384, published as U.S. Patent Application Publication 2010/0036445A1, which is incorporated herein by reference in its entirety, and/or U.S. Patent Application Serial No. 11/595,596, published as U.S. Patent Application Publication 2007/0123952A1, which is incorporated by reference herein in its entirety, and/or U.S. Patent Application Serial No.
  • Control of a stimulator and/or stimulation parameters according to the present invention may be provided by one or more external controllers.
  • the controller may be integrated with the external stimulator.
  • an implanted pulse generator external controller i.e., clinical programmer
  • an implanted pulse generator external controller may be a remote unit that uses RF (Radio Frequency) wireless telemetry communications (rather than an inductively coupled telemetry) to control the implanted pulse generator.
  • the external or implantable pulse generator may use passive charge recovery to generate the stimulation waveform, regulated voltage (e.g., 10 mV to 20 V), and/or regulated current (e.g., about 10 ⁇ to about 50 mA) .
  • Passive charge recovery is one method of generating a biphasic, charge-balanced pulse as desired for tissue stimulation without severe side effects due to a DC component of the current.
  • the neurostimulation pulse may by monophasic, biphasic, and/or multi-phasic.
  • the pulse may be symmetrical or asymmetrical.
  • Its shape may be rectangular or exponential or a combination of rectangular and exponential waveforms.
  • the pulse width of each phase may range between e.g., about 0.1 ⁇ . to about 1.0 sec, as non-limiting examples.
  • the preferred neurostimulation waveform is cathodic stimulation (though anodic may work), biphasic, and asymmetrical.
  • Pulses may be applied in continuous or intermittent trains (i.e., the stimulus frequency changes as a function of time) .
  • the on/off duty cycle of pulses may be symmetrical or asymmetrical, and the duty cycle may be regular and repeatable from one intermittent burst to the next or the duty cycle of each set of bursts may vary in a random (or pseudo random) fashion. Varying the stimulus frequency and/or duty cycle may assist in warding off habituation because of the stimulus modulation.
  • the stimulating frequency may range from e.g., about 1 Hz to about 300 Hz, or even as high as about 20 kHz to obtain a stochastic response, and the frequency of stimulation may be constant or varying. In the case of applying stimulation with varying frequencies, the frequencies may vary in a consistent and repeatable pattern or in a random (or pseudo random) fashion or a combination of repeatable and random patterns.
  • the stimulator is set to an intensity (e.g. l-2mA (or 0.1-40mA, or 0.01- 200mA), 100-300us (or 40-1000us, or l-10,000us)) sufficient to activate the targeted efferent or afferent neural structures, using an electrode that is preferably spaced at some distance (e.g. 1 mm) away from the targeted structure. Additionally or alternatively, an electrode may be placed in direct contact with a target neural structure. If the stimulus intensity is too great, it may generate large muscle twitches or contractions sufficient to disrupt correct placement of the lead.
  • an intensity e.g. l-2mA (or 0.1-40mA, or 0.01- 200mA
  • 100-300us or 40-1000us, or l-10,000us
  • the lead may be advanced too close to the targeted nerve of passage (beyond the optimal position) , possibly leading to incorrect guidance, nerve damage, mechanically evoked sensation (e.g. pain and/or paresthesia) and/or muscle contraction, inability to activate the target nerve fiber (s) without activating non-target nerve fiber (s), improper placement, and/or improper anchoring of the lead (e.g. the lead may be too close to the neural structure and no longer able to anchor appropriately in the targeted anchoring tissue, such as muscle or adipose tissue) .
  • the targeted anchoring tissue such as muscle or adipose tissue
  • the stimulator may be set to a frequency (e.g. 0.5-12Hz (or 0.1-20Hz, or 0.05-40Hz)) low enough to evoke visible muscle twitches (i.e. non-fused muscle contraction) and/or muscle contraction ( s ) of the targeted muscle (s) innervated by the target nerve of passage, but high enough that that the targeted nerve will be activated before the lead is advanced beyond an optimal position, preferably spaced from the nerve.
  • a frequency e.g. 0.5-12Hz (or 0.1-20Hz, or 0.05-40Hz)
  • the lead (non- limiting examples of the lead could include a single or multi-contact electrode that is designed for temporary (percutaneous) or long-term (implant) use or a needle electrode (used for in-office testing only) ) may be advanced (e.g. slowly advanced) towards the targeted nerve until a desired indicator response (e.g. muscle twitch, muscle contraction, patient sensation, and/or some combination) is obtained, thereby defining an optimal placement position. The intensity may then be decreased (e.g. gradually decreased) as the lead is advanced (e.g.
  • the desired indicator response (s) may be obtained at smaller intensity (ies) within the target range (e.g. 0.1-1.0mA (or 0.09-39mA, or 0.009-199mA) , 100-300us (or 40-1000us, or 1- 10,000us)) at some distance (e.g. X2 mm, where X2 ⁇ XI, and (as a non- limiting example) XI may be multiple times larger than X2, such as XI > 2*X2, or XI > 5*X2, or XI > 20*X2 ) from the target nerve.
  • specific response (s) e.g.
  • the lead may be located in a non-optimal location (e.g. too close to the target nerve (s) ) .
  • ranges of intensities that may be considered too low include those that are a fraction (e.g. ⁇ 2/3, or ⁇ 1/5, or ⁇ 1/10) of the intensities that obtained the desired response (s) at XI.
  • the preferred stimulus intensities are a function of many variables, are meant to serve as non- limiting examples only, and may need to be scaled accordingly. As an example, if electrode shape, geometry, or surface area were to change, then the stimulus intensities may need to change appropriately. For example, if the intensities were calculated for a lead with an electrode surface area of approximately 20 mm 2 , then they may need to be scaled down accordingly to be used with a lead with an electrode surface area of 0.2 mm 2 because a decrease in stimulating surface area may increase the current density, increasing the potential to activate excitable tissue (e.g. target and non-target nerve (s) and/or fiber (s) ) .
  • excitable tissue e.g. target and non-target nerve (s) and/or fiber (s)
  • the intensities may need to be scaled up accordingly to be used with a lead with an electrode surface area of 20 mm 2 .
  • stimulus intensities may need to be scaled to account for variations in electrode shape or geometry (between or among electrodes) to compensate for any resulting variations in current density.
  • the electrode contact surface area may be 0.1-20mm 2 , 0.01-40mm 2 , or 0.001-200mm 2 .
  • the electrode contact configuration may include one or more of the following characteristics: cylindrical, conical, spherical, hemispherical, circular, triangular, trapezoidal, raised (or elevated) , depressed (or recessed), flat, and/or borders and/or contours that are continuous, intermittent (or interrupted), and/or undulating.
  • Stimulus intensities may need to be scaled to account for biological factors, including but not limited to patient body size, weight, mass, habitus, age, and/or neurological condition (s) .
  • patients that are older have a higher body-mass index (BMI), and/or neuropathy (e.g. due to diabetes) may need to have stimulus intensities scaled higher (or lower) accordingly .
  • BMI body-mass index
  • neuropathy e.g. due to diabetes
  • stimulation may be unable to evoke the desired response (e.g. muscle contraction (s) , comfortable sensation (s) , and/or pain relief) in the desired region (s) at the desired stimulus intensity (ies) .
  • stimulation may be unable to evoke the desired response (s) (e.g. muscle contraction (s) , comfortable sensation (s) , and/or pain relief) in the desired region (s) at the desired stimulus intensity (ies) without evoking undesirable response (s) (e.g.
  • alternative stimulus waveforms and/or combinations of leads and/or electrode contacts may be used.
  • alternative stimulus waveforms may include the use of a pre-pulse to increase the excitability of the target fiber (s) and/or decrease the excitability of the non-target fiber (s) .
  • Pain relief provided by systems and methods according to the present invention may be correlated to an analysis of quality of life of the animal receiving such relief. It may be important to measure the health- related quality of life (HRQOL) , as pain is known to impact even otherwise simple, daily activities.
  • HRQOL health- related quality of life
  • One methodology includes analysis of patient responses to one or more questions from an SF-36 Health Survey, available from Quality Metric, Inc., of Lincoln, Rhode Island.
  • the SF-36 is a generic health survey of 36 items designed to assess basic physical functioning and emotional well-being regardless of the disease or treatment.
  • the 36 items are grouped into eight domains: physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health perceptions .
  • the items include questions related to the following:
  • the ratings provided by the patient are on scales of, e.g., 1 to 3, or 1 to 5.
  • PDI Pain Disability Index
  • Chores and errands This category refers to activities of related generally to home life and/or family. It includes chores or duties performed around the house (e.g., yard work, dusting, laundry) and errands or favors for other family members (e.g., driving the children to school, grocery shopping);
  • This category refers to interaction with friends and acquaintances other than family members, such as attendance at parties, a theater, concerts, restaurants, and other social functions;
  • Job-related activities This category refers to activities that are a part of or directly related to one's job, whether or not it is a paying, non-paying or volunteer career;
  • This category refers to the frequency and quality of one's sex life
  • This category includes activities related to independent daily living (e.g. taking a shower, driving, getting dressed, shaving, etc . ) ; and
  • Life-sustaining behavior This category refers to basic behaviors such as eating, sleeping, and breathing .
  • BPI-SF Brief Pain Inventory-Short Form
  • BPI-LF Brief Pain Inventory- Long Form
  • BPI-SF question number 3 requests that patients rate the worst pain they have experienced in the past week on a scale from zero to ten, where zero indicates "no pain” and ten indicates "pain as bad as you can imagine.”
  • BPI-SF question 9 requests that patients rate, on a scale of zero to ten, the interference of pain on various activities. A rating of zero indicates that pain has no interference on the activity and a rating of ten indicates that pain completely interferes with such activity.
  • Such survey may include ratings of interference on activities such as general activity, walking ability, normal work (inside and outside the home) , sleep, and interpersonal relations. Further such survey may include ratings of personal feelings, such as the pain interference with mood or enjoyment of life. Where all seven eleven-point- scale ratings are included, a mean score between zero and ten may be calculated by summing the seven ratings and dividing by seven.
  • the quality of life surveys are preferably administered both before and after a treatment period, and the results thereof are compared.
  • a comparison of the post-treatment mean and the pre-treatment mean may indicate a level of success of the treatment.
  • post-treatment may refer to any time after the start of treatment, including but not limited to after completion of a treatment period, duration, regime, or protocol.
  • eleven-point (0-10) mean scale of the BPI-SF question 9 it is preferable to have an improvement (reduction) of more than one point out of the total ten possible points, more preferably to have an improvement of more than two points, and most preferred to have an improvement of more than three points.
  • stimulation parameters or methodologies may be altered, and the quality of life may again be examined, and compared to baseline (prior to receipt of any treatment) and/or to other post-treatment results to determine whether the altered parameters were any more or less effective than the first in improving quality of life.

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Abstract

Des modes de réalisation de la présente invention concernent des systèmes et procédés pour le traitement de la douleur par activation de fibres neurales sélectionnées. Les fibres neurales peuvent comprendre une ou plusieurs fibres neurales afférentes et/ou une ou plusieurs fibres neurales efférentes. Si des fibres afférentes sont stimulées, seules ou combinées à des fibres efférentes, une quantité thérapeutiquement efficace est appliquée pour activer des chemins afférents d'une manière approchant l'activité afférente naturelle. Les fibres afférentes peuvent être associés à des récepteurs primaires de fuseaux musculaires, d'organes tendineux de Golgi, de récepteurs secondaire de fuseaux musculaires, de récepteurs d'articulations, de récepteurs tactiles et d'autres types de mécanorécepteurs et/ou propriorécepteurs. Si des fibres efférentes sont stimulées, seules ou combinées à des fibres afférentes, une quantité thérapeutiquement efficace est appliquée pour activer des fibres intrafusales et/ou extrafusales musculaires, ce qui résulte en une activation indirecte de fibres afférentes qui leur sont associées.
PCT/US2011/062882 2010-12-01 2011-12-01 Systèmes et procédés pour le traitement de la douleur par stimulation des fibres neurales Ceased WO2012075281A1 (fr)

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AU2011336430B2 (en) 2016-09-29

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